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  • 1. Anderson, Kristina
    et al.
    Rusterholz, Corinne
    Månsson, Robert
    Jensen, Christina T
    Bacos, Karl
    Sasan, Zandi
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Sasaki, Yutaka
    Nerlov, Claus
    Sigvardsson, Mikael
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Jacobsen, Sten Eirik W
    Ectopic expression of PAX5 promotes maintenance of biphenotypic myeloid progenitors coexpressing myeloid and B-cell lineage-associated genes2007Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, nr 9, s. 3697-3705Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transcription factor PAX5 is a critical regulator of B-cell commitment and development. Although normally not expressed in myeloid progenitors, PAX5 has recently been shown to be frequently expressed in myeloid malignancies and to suppress expression of myeloid differentiation genes, compatible with an effect on the differentiation or maintenance of myeloid progenitors. However, previous studies in which PAX5 was ectopically expressed in normal myeloid progenitors in vivo and in vitro provided conflicting results as to the effect of PAX5 on myeloid development. Herein, we demonstrate that on ectopic expression of PAX5 in bone marrow multipotent stem/progenitor cells, cells with a biphenotypic B220+GR-1/MAC-1+ phenotype are produced. These remain cytokine-dependent, but unlike control-transduced cells they sustain long-term generation of myeloid progenitors in vitro and remain capable of myeloid differentiation. Notably, PAX5+B220+GR-1/MAC- 1+ myeloid progenitors coexpress, at the single-cell level, myeloid genes and otherwise B-cell-specific PAX5 target genes. These findings establish that ectopic expression of PAX5 introduces extensive self-renewal properties in otherwise short-lived myeloid progenitors. Along with the established ectopic expression of PAX5 in acute myeloid leukemia, this motivates a careful investigation of the potential involvement of ectopic PAX5 expression in myeloid and biphenotypic leukemias. © 2007 by The American Society of Hematology.

  • 2.
    Björnsson, Jon Mar
    et al.
    Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University.
    Andersson, Elisabet
    Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University.
    Lundström, Patrik
    Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University.
    Larsson, Nina
    Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University.
    Xu, Xiufeng
    Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University.
    Repetowska, Ewa
    Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University.
    Humphries, R. Keith
    Terry Fox Laboratory, British Columbia Cancer Agency.
    Karlsson, Stefan
    Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University.
    Proliferation of primitive myeloid progenitors can be reversibly  induced by HOXA102001Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 98, nr 12, s. 3301-3308Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies show that several Hox transcription factors are important for regulation of proliferation and differentiation in hematopoiesis. Among these is H0XA10, which is selectively expressed at high levels in the most primitive subpopulation of human CD34+ bone marrow cells. When overexpressed, H0XA10 increases the proliferation of early progenitor cells and can lead to the development of myeloid leukemia. To study the effects of H0XA10 on primitive hematopoietic progenitors in more detail, transgenic mice were generated with regulatable H0XA10 expression. The transgenic mouse model, referred to astetO-HOXA10, contains theH0XA10 gene controlled by a tetracycline-responsive element and a minimal promoter. Thus, the expression of H0XA10 is inducible and reversible depending on the absence or presence of tetracycline or its analog, doxycycline. A retroviral vector containing the tetracycline transactivator gene (tTA) was used to induce expression of the H0XA10 gene in bone marrow cells from the transgenic mice. Reverse transcription–polymerase chain reaction analysis confirmed regulatable H0XA10 expression in several transgenic lines. H0XA10 induction led to the formation of hematopoietic colonies containing blastlike cells and megakaryocytes. Moreover, the induction of H0XA10 resulted in significant proliferative advantage of primitive hematopoietic progenitors (spleen colony-forming units [CFUS12]), which was reversible on withdrawal of induction. Activation of H0XA10 expression in tet0-H0XA10 mice will therefore govern proliferation of primitive myeloid progenitors in a regulated fashion. This novel animal model can be used to identify the target genes of HOXA10 and better clarify the specific role of HOXA10 in normal and malignant hematopoiesis.

  • 3.
    Björnsson, Jon Mar
    et al.
    Lund University, Department of Molecular Medicine.
    Larsson, Nina
    Lund University, Department of Molecular Medicine.
    Brun, Ann C. M.
    Lund University, Department of Molecular Medicine.
    Andersson, Elisabet
    Lund University, Department of Molecular Medicine.
    Lundström, Patrik
    Lund University, Department of Molecular Medicine.
    Larsson, Jonas
    Lund University, Department of Molecular Medicine.
    Repetowska, Ewa
    Lund University, Department of Molecular Medicine.
    Ehinger, Mats
    Lund University, Department of Molecular Medicine.
    Humphries, R. Keith
    University of British Columbia, Department of Medicine.
    Karlsson, Stefan
    Lund University, Department of Molecular Medicine.
    Reduced proliferative capacity of hematopoietic stem cells deficient in hoxb3 and hoxb42003Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 23, nr 11, s. 3872-3883Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several homeobox transcription factors, such as HOXB3 and HOXB4, have been implicated in regulation of hematopoiesis. In support of this, studies show that overexpression of HOXB4 strongly enhances hematopoietic stem cell regeneration. Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment. Analysis of embryonic day 14.5 fetal livers revealed a significant reduction in the hematopoietic stem cell pool, suggesting that the reduction in cellularity observed postnatally is due to insufficient expansion during fetal development. Primitive Lin(-) Scal(+) c-kit(+) hematopoietic progenitors lacking Hoxb3 and Hoxb4 displayed impaired proliferative capacity in vitro. Similarly, in vivo repopulating studies of Hoxb3/Hoxb4-deficient hematopoietic cells resulted in lower repopulating capability compared to normal littermates. Since no defects in homing were observed, these results suggest a slower regeneration of mutant HSC. Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs. Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response.

  • 4.
    Boknäs, Niklas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Ström, Jakob O
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    Sahlgrenska Academy, University of Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas L
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 10, s. 1692-1694Artikkel i tidsskrift (Annet vitenskapelig)
  • 5.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Ierardi, Rossella
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milano, Italy.
    Alborelli, Ilaria
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Fugazza, Cristina
    John Radcliffe Hospital, Molecular Hematology Unit, Oxford, United Kingdom.
    Cassinelli, Letizia
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Piconese, Silvia
    Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
    Bosè, Francesca
    5INGM-Fondazione Istituto Nazionale di Genetica molecolare, Milano, Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Ferrari, Giuliana
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milano, Italy / Universita` Vita-Salute San Raffaele, Milano, Italy.
    Ronchi, Antonella
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Sox6 enhances erythroid differentiation in human erythroid progenitors.2011Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, nr 13, s. 3669-79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sox6 belongs to the Sry (sex-determining region Y)-related high-mobility-group-box family of transcription factors, which control cell-fate specification of many cell types. Here, we explored the role of Sox6 in human erythropoiesis by its overexpression both in the erythroleukemic K562 cell line and in primary erythroid cultures from human cord blood CD34+ cells. Sox6 induced significant erythroid differentiation in both models. K562 cells underwent hemoglobinization and, despite their leukemic origin, died within 9 days after transduction; primary erythroid cultures accelerated their kinetics of erythroid maturation and increased the number of cells that reached the final enucleation step. Searching for direct Sox6 targets, we found SOCS3 (suppressor of cytokine signaling-3), a known mediator of cytokine response. Sox6 was bound in vitro and in vivo to an evolutionarily conserved regulatory SOCS3 element, which induced transcriptional activation. SOCS3 overexpression in K562 cells and in primary erythroid cells recapitulated the growth inhibition induced by Sox6, which demonstrates that SOCS3 is a relevant Sox6 effector.

  • 6. Crawley, C
    et al.
    Lalanacette, M
    Szydlo, R
    Gilleece, M
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Michallet, M
    Mackinnon, S
    Einsele, H
    Reiffers, J
    Zander, AR
    Carreras, E
    Carella, A
    Gratwohl, A
    Sotto, JJ
    Cavenagh, JD
    Niederweiser, D
    Ciceri, F
    Apperley, JF
    Reduced intensity conditioned allografts for myeloma: A study from the Chronic Leukaemia Working Party of the EBMT.2002Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, nr 11, s. 542-Konferansepaper (Annet vitenskapelig)
  • 7. Crawley, C
    et al.
    Lalancette, M
    Szydlo, R
    Gilleece, M
    Peggs, K
    Mackinnon, S
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Ahlberg, Lucia
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Nagler, A
    Shimoni, A
    Sureda, A
    Boiron, JM
    Einsele, H
    Chopra, R
    Carella, A
    Cavenagh, J
    Gratwohl, A
    Garban, F
    Zander, A
    Bjorkstrand, B
    Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT2005Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, nr 11, s. 4532-4539Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report the outcome of 229 patients who received an allograft for myeloma with reduced-intensity conditioning (RIC) regimens from 33 centers within the European Group for Blood and Marrow Transplantation (EBMT). The median age was 52 years and 64% were male. Conditioning regimens were heterogeneous, but most were fludarabine based and T cell depleted with antithymocyte globulin or alemtuzumab. Transplantation-related mortality (TRIM) at 1 year was 22%. The 3-year overall survival (OS) and progression-free survival (PFS) were 41% and 21 %, respectively. Adverse OS was associated with chemoresistant disease (relative risk [RR], 2.9), more than 1 prior transplantation (RR, 2.0), and male patients with female donors (FIR, 1.45). Adverse PFS was associated with chemoresistance (RR, 2.4) and alemtuzumab (RR, 1.8). TRM was increased with female-to-male donation (RR, 2.5) and transplantation more than 1 year from diagnosis (RR, 2.3). Grades II to IV acute graft-versus-host disease (aGvHD) occurred in 31%. Chronic GvHD was associated with better OS and PFS and were 84% and 46% for limited, 58% and 30% for extensive, and 29% and 12% in its absence suggesting that a graft-versus-myeloma effect is important. While RIC is feasible, heavily pretreated patients and patients with progressive disease do not benefit.

  • 8. Crawley, C
    et al.
    Szydlo, R
    Lalancette, M
    Bacigalupo, A
    Lange, A
    Brune, M
    Juliusson, Gunnar
    Nagler, A
    Gratwohl, A
    Passweg, J
    Komarnicki, M
    Vitek, A
    Mayer, J
    Zander, A
    Sierra, J
    Rimbaldi, A
    Ringden, O
    Niederwieser, D
    Apperley, JF
    Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognóstic factors from the Chronic Leukemia Working Party of the EBMT2005Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 106, nr 9, s. 2969-2976Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study reports outcomes of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) in 186 patients with chronic myeloid leukemia (CML) from the European Group for Blood and Marrow Transplantation (EBMT). The median age was 50 years, and 64% were in first chronic phase (CP1), CP2 13%, accelerated phase 17%, and blast crises 6%. The median EBMT transplant score was 3. The day 100 transplantation-related mortality (TRM) was 6.1% (confidence interval [CI], 3.4%-11%) but rose to 23.3% (CI, 14%-27%) at 2 years. Fludarabine, busulfan, and antithymocyte globulin (Fd/Bu/ATG) was associated with the lowest TRM of 11.6% (CI, 4.7%-11%) at 1 year. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 32% and chronic GvHD in 43% (extensive in 24%). ATG was associated with a lower incidence of chronic GvHD (cGvHD). The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% (CI, 50%-66%) and 37% (CI, 30%-45%), respectively. Adverse OS was associated with advanced disease (relative risk [RR], 3.4). PFS was inferior in advanced disease (RR, 2.7) and a trend to improved outcomes with Fd/Bu/ATG (RR, 0.58). RIC allografts are feasible in CML in first or second CP. Since no other RIC regimen demonstrated superiority, Fd/Bu/ATG should be considered as baseline in future prospective trials.

  • 9. Crawley, CR
    et al.
    Lalancette, M
    Szydlo, R
    Bacigalupo, A
    Lange, A
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Ringden, O
    Gratwohl, A
    Mayer, J
    Hansz, J
    Zander, AR
    Vitek, A
    Brune, ML
    Urbano-Ispizua, A
    Niederwieser, D
    Mufti, G
    Apperley, JF
    Reduced intensity conditioned allografts for chronic myeloid leukaemia: A study from the chronic leukaemia working party of the EBMT.2002Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, nr 11, s. 3089-Konferansepaper (Annet vitenskapelig)
  • 10. De Angelo, DJ
    et al.
    Schiffer, C
    Stone, R
    Amrein, P
    Fernandez, H
    Bradstock, K
    Tallman, M
    Foran, J
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Liu, D
    Paul, C
    Russo, D
    Stenke, L
    Leopold, L
    Stevenson, D
    Richie, M
    Berger, M
    Interim analysis of a phase II study of the safety and efficacy of gemtuzumab ozogamicin (Mylotarg (R)) given in combination with cytarabine and daunorubicin to patients < 60 years old with untreated acute myeloid leukemia.2002Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, nr 11, s. 745-Konferansepaper (Annet vitenskapelig)
  • 11.
    Debatin, K. M.
    et al.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Friesen, C.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Herr, I.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Los, Marek Jan
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Activation of the CD95 pathway by anticancer drugs.1996Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 88, nr 10, s. 2641-2641Artikkel i tidsskrift (Fagfellevurdert)
  • 12. Ekoff, Maria
    et al.
    Kaufmann, Thomas
    Engström, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Motoyama, Noboru
    Villunger, Andreas
    Jönsson, Jan-Ingvar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Strasser, Andreas
    Nilsson, Gunnar
    The BH3-only protein Puma plays an essential role in cytokine deprivation-induced apoptosis of mast cells2007Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 110, nr 9, s. 3209-3217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mast cells play critical roles in the regulation of inflammation. One characteristic feature of mast cells is their relatively long lifespan in vivo. Members of the Bcl-2 protein family are regulators of cell survival and apoptosis, where the BH3-only proteins are critical proapoptotic proteins. In this study we investigated the role of the BH3-only proteins Noxa, Bad, Bim, Bmf, Bid, and Puma in apoptosis of mucosal-like mast cells (MLMCs) and connective tissue-like mast cells (CTLMCs). We demonstrate that Puma is critical for the induction of mast-cell death following cytokine deprivation and treatment with the DNA-damaging agent etoposide in MLMCs and CTLMCs. Using p53-/- mast cells, we found that cytokine deprivation-induced apoptosis, in contrast to that elicited by etoposide, is p53-independent. Interestingly, mast cells deficient in FOXO3a, previously proposed as a transcription factor for Puma induction in response to growth factor deprivation, were markedly resistant to cytokine withdrawal compared with wildtype cells. Moreover, overexpression of phosphorylation-deficient, constitutively active FOXO3a caused an up-regulation of Puma. In conclusion, our data demonstrate a pivotal role for Puma in the regulation of cytokine deprivation-induced mast-cell apoptosis and suggest a plausible role for Puma in the regulation of mast cell numbers in vivo. © 2007 by The American Society of Hematology.

  • 13.
    Faxälv, Lars
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Boknäs, Niklas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Ström, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    University of Gothenburg, Gothenburg, Sweden .
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, nr 23, s. 3818-3824Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Muller et al has been cited greater than100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of less than10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

  • 14. Fonteneau, Jean Francois
    et al.
    Kavanagh, Daniel G.
    Lirvall, Margareta
    Sanders, Catherine
    Cover, Timothy L.
    Bhardwaj, Nina
    Larsson, Marie
    Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells2003Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 102, nr 13, s. 4448-4455Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Major histocompatibility complex (MHC) class I presentation of exogenous antigens is the mechanism enabling professional antigen-presenting cells (APCs) to induce CD8+ T-cell responses against viruses and tumors that do not have access to the classical MHC class I pathway. We have characterized the uptake, processing, and MHC class I cross-presentation by human dendritic cells (DCs) of cell-associated antigens derived from physiologically relevant sources, namely, vaccinia virus-infected apoptotic and necrotic cells. We show that cross-presentation is a rapid process, detectable within 2 to 4 hours after uptake of dead cells, and that proteolysis by cathepsin D in an acidic endosomal compartment is essential for cross-presentation. The presentation is abolished when the phagocytic or macropinocytic functions of the cells are inhibited and is dependent on transporter associated with antigen processing, sensitive to brefeldin A, and requires functional proteasomes. Altogether, these data suggest that antigens derived from apoptotic and necrotic cells require access to the cytosol to intersect with the conventional MHC class I pathway for presentation of cytosolic proteins.

  • 15. Fotoohi, K
    et al.
    Jansen, G
    Assaraf, Y G
    Rothem, L
    Stark, M
    Kathmann, L
    Gregorczyk, J
    Peters, G J
    Albertioni, Freidoun
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7 - hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy2004Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 104, s. 4194-4201Artikkel i tidsskrift (Fagfellevurdert)
  • 16.
    Fulda, S.
    et al.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Friesen, C.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Benedict, M.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Nunez, G.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Peter, M. E.
    UNIV ULM, CHILDRENS HOSP, ULM, GERMANY .
    Debatin, K. M.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    CD95 (APO-1/Fas)- and p53-independent apoptosis by betulinic acid involves mitochondrial alterations and activation of caspases.1997Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 90, nr 10, s. 2207-2207Artikkel i tidsskrift (Fagfellevurdert)
  • 17.
    Grabowski, Pawel
    et al.
    Umeå University.
    Hultdin, Magnus
    Karlsson, Karin
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Tobin, Gerard
    Uppsala University.
    Åleskog, Anna
    Uppsala University.
    Thunberg, Ulf
    Uppsala University.
    Laurell, Anna
    Uppsala University.
    Sundström, Christer
    Uppsala University.
    Rosenquist, Richard
    Uppsala University.
    Roos, Göran
    Umeå University.
    Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status2005Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, nr 12, s. 4807-4812Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improvedsubclassification of CLL was achieved identifying previouslyunrecognized patient groups with different outcomes. (Blood.2005;105:4807-4812)

  • 18.
    Gregers, Jannie
    et al.
    University of Copenhagen, Denmark.
    Jarle Christensen, Ib
    Rigshospital, Copenhagen, Denmark.
    Dalhoff, Kim
    Bispebjerg Hospital.
    Lausen, Birgitte
    Rigshospital, Copenhagen, Denmark.
    Schroeder, Henrik
    Rigshospital, Copenhagen, Denmark.
    Rosthoej, Steen
    Rigshospital, Aalborg, Denmark.
    Carlsen, Niels
    Rigshospital, Odense, Denmark.
    Schmiegelow, Kjeld
    University of Copenhagen, Denmark.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number2010Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 23, s. 4671-4677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G greater than A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G greater than A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

  • 19.
    Guidez, F
    et al.
    Chester Beatty Laboratories, London, UK.
    Ivins, S
    Chester Beatty Laboratories, London, UK.
    Zhu, J
    Chester Beatty Laboratories, London, UK.
    Söderström, Mats
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Waxman, S
    Mount Sinai School of Medicine, New York, USA.
    Zelent, A
    Chester Beatty Laboratories, London, UK.
    Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia1998Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 91, nr 8, s. 2634-2642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARalpha fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARalpha fusion protein. Both PML- and PLZF-RARalpha possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARalpha protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARalpha, it had a very little effect on its association with the PLZF-RARalpha fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARalpha fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARalpha on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARalpha-associated leukemias to ATRA.

  • 20. Hedlund, M
    et al.
    Bengtson, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Pahlsson, P
    Leffler, H
    Galectin mediated tethering and neutrophil leukocyte arrest under laminar flow conditions.2002Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, nr 11, s. 549-Konferansepaper (Annet vitenskapelig)
  • 21.
    Heenkenda, Menikae K.
    et al.
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Frequency of PAR4 Ala120Thr variant associated with platelet reactivity significantly varies across sub-Saharan African populations2018Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132, nr 19, s. 2103-2106Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 22.
    Hoglund, Martin
    et al.
    University of Uppsala Hospital, Sweden .
    Sandin, Fredrik
    Regional Cancer Centre, Sweden .
    Hellstrom, Karin
    Regional Cancer Centre, Sweden .
    Bjoreman, Mats
    University Hospital, Sweden .
    Bjorkholm, Magnus
    Karolinska University Hospital, Sweden .
    Brune, Mats
    Sahlgrens University Hospital, Sweden .
    Dreimane, Arta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ekblom, Marja
    Skåne University Hospital, Sweden .
    Lehmann, Soren
    Karolinska University Hospital, Sweden .
    Ljungman, Per
    Karolinska University Hospital, Sweden .
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Markevarn, Berit
    Umeå University Hospital, Sweden .
    Myhr-Eriksson, Kristina
    Sunderby Luleå Hospital, Sweden .
    Ohm, Lotta
    Karolinska University Hospital, Sweden .
    Olsson-Stromberg, Ulla
    University of Uppsala Hospital, Sweden .
    Sjalander, Anders
    Umeå University, Sweden .
    Wadenvik, Hans
    Sahlgrens University Hospital, Sweden .
    Simonsson, Bengt
    University of Uppsala Hospital, Sweden .
    Stenke, Leif
    Karolinska University Hospital, Sweden .
    Richter, Johan
    Skåne University Hospital, Sweden .
    Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, nr 7, s. 1284-1292Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100 000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (andlt;70 years) and 79% for older (andgt;80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.

  • 23.
    Jensen, Christina T.
    et al.
    Lund University.
    Böiers, Charlotta
    Lund University.
    Kharazi, Shabnam
    Lund University.
    Lübking, Anna
    Lund University.
    Rydén, Tobias
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Sitnicka, Ewa
    Lund University.
    Jacobsen, Sten Eirik W.
    Lund University.
    Permissive roles of hematopoietin and cytokine tyrosine kinase receptors in early T-cell development2008Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, nr 4, s. 2083-2090Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although several cytokines have been demonstrated to be critical regulators of development of multiple blood cell lineages, it remains disputed to what degree they act through instructive or permissive mechanisms. Signaling through the FMS-like tyrosine kinase 3 (FLT3) receptor and the hematopoietin IL-7 receptor alpha (IL-7Ralpha) has been demonstrated to be of critical importance for sustained thymopoiesis. Signaling triggered by IL-7 and thymic stromal lymphopoietin (TSLP) is dependent on IL-7Ralpha, and both ligands have been implicated in T-cell development. However, we demonstrate that, whereas thymopoiesis is abolished in adult mice doubly deficient in IL-7 and FLT3 ligand (FLT3L), TSLP does not play a key role in IL-7-independent or FLT3L-independent T lymphopoiesis. Furthermore, whereas previous studies implicated that the role of other cytokine tyrosine kinase receptors in T lymphopoiesis might not involve permissive actions, we demonstrate that ectopic expression of BCL2 is sufficient not only to partially correct the T-cell phenotype of Flt3l(-/-) mice but also to rescue the virtually complete loss of all discernable stages of early T lymphopoiesis in Flt3l(-/-)Il7r(-/-) mice. These findings implicate a permissive role of cytokine receptors of the hematopoietin and tyrosine kinase families in early T lymphopoiesis. 

  • 24.
    Juliusson, Gunnar
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Celsing, F
    Linkoping Univ Hosp, S-58185 Linkoping, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden Univ Hosp MAS, Malmo, Sweden Cty Hosp, Kalmar, Sweden.
    Turesson, I
    Linkoping Univ Hosp, S-58185 Linkoping, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden Univ Hosp MAS, Malmo, Sweden Cty Hosp, Kalmar, Sweden.
    Adriansson, M
    Linkoping Univ Hosp, S-58185 Linkoping, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden Univ Hosp MAS, Malmo, Sweden Cty Hosp, Kalmar, Sweden.
    Malm, C
    Thalidomide frequently induces good partial remission and best response ever in patients with advanced myeloma and prior high dose melphalan and autotransplant.1999Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 94, nr 10, s. 546-Konferansepaper (Annet vitenskapelig)
  • 25.
    Juliusson, Gunnar
    et al.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Hagberg, Oskar
    Lund Univ, Sweden.
    Lazarevic, Vladimir Lj
    Skane Univ Hosp, Sweden.
    Olander, Emma
    Sundsvall Hosp, Sweden.
    Antunovic, Petar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Cammenga, Jörg
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Brune, Mats
    Sahlgrens Univ Hosp, Sweden.
    Jadersten, Martin
    Karolinska Univ Hosp, Sweden.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden.
    Lehmann, Soren
    Karolinska Univ Hosp, Sweden; Uppsala Univ, Sweden.
    Derolf, Asa Rangert
    Karolinska Univ Hosp, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Improved survival of men 50 to 75 years old with acute myeloid leukemia over a 20-year period2019Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 134, nr 18, s. 1558-1561Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 26.
    Juliusson, Gunnar
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Karlsson, K
    Frodin, U
    Backstrom, G
    Malm, Claes
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Subcutaneous Campath1H instead of thymoglobulin in nonmyeloablative allogeneic transplantation: Reduced acute toxicity, but delayed lymphocyte recovery leading to more mixed chimerism, more fatal infections and impaired long-term survival2002Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, nr 11, s. 1665-Konferansepaper (Annet vitenskapelig)
  • 27.
    Juliusson, Gunnar
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Lofgren, CR
    Univ Hosp, Linkoping, Sweden Huddinge Univ Hosp, S-14186 Huddinge, Sweden Acad Hosp, Uppsala, Sweden Med Ctr Hosp, Orebro, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden.
    Mollgard, L
    Univ Hosp, Linkoping, Sweden Huddinge Univ Hosp, S-14186 Huddinge, Sweden Acad Hosp, Uppsala, Sweden Med Ctr Hosp, Orebro, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden.
    Paul, C
    Univ Hosp, Linkoping, Sweden Huddinge Univ Hosp, S-14186 Huddinge, Sweden Acad Hosp, Uppsala, Sweden Med Ctr Hosp, Orebro, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden.
    Hoglund, M
    Tidefelt, U
    Univ Hosp, Linkoping, Sweden Huddinge Univ Hosp, S-14186 Huddinge, Sweden Acad Hosp, Uppsala, Sweden Med Ctr Hosp, Orebro, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden.
    Bjorkholm, M
    Univ Hosp, Linkoping, Sweden Huddinge Univ Hosp, S-14186 Huddinge, Sweden Acad Hosp, Uppsala, Sweden Med Ctr Hosp, Orebro, Sweden Karolinska Hosp, S-10401 Stockholm, Sweden.
    No additional toxicity from cladribine (CdA) when given with cytosin arabinoside and idarubicin (CCI) as primary treatment of acute myeloid leukemia in elderly patients: Results from a randomized phase II-study from the leukemia group of middle Sweden (LGMS).2001Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 98, nr 11, s. 518-Konferansepaper (Annet vitenskapelig)
  • 28.
    Kimby, E
    et al.
    Huddinge Univ Hosp, S-14186 Huddinge, Sweden Univ Lund Hosp, S-22185 Lund, Sweden Linkoping Univ Hosp, S-58185 Linkoping, Sweden Univ Uppsala Hosp, Uppsala, Sweden Univ Umea Hosp, S-90185 Umea, Sweden Univ Hosp Stockholm, Stockholm, Sweden Malmo Univ Hosp, Malmo, Sweden.
    Cavallin-Stahl, E
    Huddinge Univ Hosp, S-14186 Huddinge, Sweden Univ Lund Hosp, S-22185 Lund, Sweden Linkoping Univ Hosp, S-58185 Linkoping, Sweden Univ Uppsala Hosp, Uppsala, Sweden Univ Umea Hosp, S-90185 Umea, Sweden Univ Hosp Stockholm, Stockholm, Sweden Malmo Univ Hosp, Malmo, Sweden.
    Haapaniemi, E
    Huddinge Univ Hosp, S-14186 Huddinge, Sweden Univ Lund Hosp, S-22185 Lund, Sweden Linkoping Univ Hosp, S-58185 Linkoping, Sweden Univ Uppsala Hosp, Uppsala, Sweden Univ Umea Hosp, S-90185 Umea, Sweden Univ Hosp Stockholm, Stockholm, Sweden Malmo Univ Hosp, Malmo, Sweden.
    Hagberg, H
    Osterman, B
    Huddinge Univ Hosp, S-14186 Huddinge, Sweden Univ Lund Hosp, S-22185 Lund, Sweden Linkoping Univ Hosp, S-58185 Linkoping, Sweden Univ Uppsala Hosp, Uppsala, Sweden Univ Umea Hosp, S-90185 Umea, Sweden Univ Hosp Stockholm, Stockholm, Sweden Malmo Univ Hosp, Malmo, Sweden.
    Tullgren, O
    Huddinge Univ Hosp, S-14186 Huddinge, Sweden Univ Lund Hosp, S-22185 Lund, Sweden Linkoping Univ Hosp, S-58185 Linkoping, Sweden Univ Uppsala Hosp, Uppsala, Sweden Univ Umea Hosp, S-90185 Umea, Sweden Univ Hosp Stockholm, Stockholm, Sweden Malmo Univ Hosp, Malmo, Sweden.
    Turesson, I
    Huddinge Univ Hosp, S-14186 Huddinge, Sweden Univ Lund Hosp, S-22185 Lund, Sweden Linkoping Univ Hosp, S-58185 Linkoping, Sweden Univ Uppsala Hosp, Uppsala, Sweden Univ Umea Hosp, S-90185 Umea, Sweden Univ Hosp Stockholm, Stockholm, Sweden Malmo Univ Hosp, Malmo, Sweden.
    Liliemark, J
    Huddinge Univ Hosp, S-14186 Huddinge, Sweden Univ Lund Hosp, S-22185 Lund, Sweden Linkoping Univ Hosp, S-58185 Linkoping, Sweden Univ Uppsala Hosp, Uppsala, Sweden Univ Umea Hosp, S-90185 Umea, Sweden Univ Hosp Stockholm, Stockholm, Sweden Malmo Univ Hosp, Malmo, Sweden.
    Fludarabine in combination with idarubicin as treatment of untreated and relapsed low-grade lymphoma. Preliminary results of a multicenter phase II study.1999Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 94, nr 10, s. 416-Konferansepaper (Annet vitenskapelig)
  • 29.
    Lalancette, M
    et al.
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Rezvani, K
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Szydlo, R
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Mackinnon, S
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Michallet, M
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Slavin, S
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Frassoni, F
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Niederwieser, D
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Gahrton, G
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Apperley, J
    Hammersmith Hosp, London, England UCL, London, England Linkoping Univ Hosp, S-58185 Linkoping, Sweden Hop Edouard Herriot, Lyon, France Hadassah Univ Hosp, IL-91120 Jerusalem, Israel Osped San Martino Genova, Genoa, Italy Univ Leipzig, D-7010 Leipzig, Germany Huddinge Univ Hosp, S-14186 Huddinge, Sweden.
    Excellent outcome of non-myeloablative stem cell transplant (NMSCT) for good risk myeloma: The EBMT experience.2000Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 96, nr 11, s. 872-Konferansepaper (Annet vitenskapelig)
  • 30.
    Lanemo Myhrinder, Anna
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Hellqvist, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Sidorova, Ekaterina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Söderberg, Anita
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Baxendale, Helen
    Infectious Disease & Microbiology Unit, Institute of Child Health, University of London Medical School, London, United Kingdom.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Willander, Kerstin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Tobin, Gerard
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Bäckman, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Söderberg, Ola
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hörkko, Sohvi
    Department of Pharmacology and Toxicology and Biocenter Oulu, University of Oulu, and Clinical Research Center, Oulu University Hospital, Oulu, Finland.
    Rosén, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies2008Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, nr 7, s. 3838-3848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The restricted immunoglobulin (Ig) repertoire found in B-cell chronic lymphocytic leukemia (CLL) implies a role for antigen(s) in the leukemogenesis. The nature of the antigens has, however, not been characterized, although examples of autoantigens have been demonstrated. We have analyzed a panel of 28 CLL cell lines and primary cultures, producing monoclonal Ig with different Ig heavy-chain variable region gene usage and mutational status, including several complementarity determining region 3 homology subset members. Using mass-spectrometry, immunoassays, or protein macroarrays, we have discovered novel antigens binding to CLL Igs. These antigens included cytoskeletal proteins vimentin, filamin B, and cofilin-1, but also phosphorylcholine-containing antigens (eg, Streptococcus pneumoniae polysaccharides and oxidized low-density lipoprotein [oxLDL]). Additional new antigens identified were cardiolipin and proline-rich acidic protein-1. Remarkably, these antigens represent molecular motifs exposed on apoptotic cells/blebs and bacteria, and several CLL Igs bound to apoptotic Jurkat cells. In conclusion, these intriguing data, showing a limited target structure recognition, indicate that CD5+ CLL B cells are derived from a cell compartment that produces "natural antibodies," which may be instrumental in elimination and scavenging of apoptotic cells and pathogenic bacteria.

  • 31. Lenhoff, Stig
    et al.
    Hjorth, Martin
    Holmberg, Erik
    Turesson, Ingemar
    Westin, Jan
    Lanng Nielsen, Johan
    Wislöff, Finn
    Brinch, Lorentz
    Carlson, Kristina
    Carlsson, Margaretha
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Dahl, Inger-Marie
    Gimsing, Peter
    Hippe, Erik
    Johnsen, Hans
    Lamvik, Jon
    Löfvenberg, Eva
    Nesthus, Ingerid
    Rödjer, Stig
    Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study.2000Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 95Artikkel i tidsskrift (Fagfellevurdert)
  • 32.
    Liliemark, E
    et al.
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Wang, Y
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Tidefelt, U
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Paul, C
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Gruber, A
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Stenke, Lilian
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan.
    Frostvik-Stolt, M
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Zhou, R
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Sundman-Engberg, B
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Gustavsson, B
    Pfister, C
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Liliemark, J
    Orebro Med Ctr Hosp, Orebro, Sweden Huddinge Hosp, S-14186 Huddinge, Sweden Karolinska Hosp, Stockholm, Sweden Linkoping Univ, S-58183 Linkoping, Sweden.
    Etoposide accumulation of AML cells is affected by PSC 833 in vivo and in vitro.1999Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 94, nr 10, s. 4055-Konferansepaper (Annet vitenskapelig)
  • 33.
    Los, Marek Jan
    et al.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Coy, J.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Walczak, H.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Debatin, K. M.
    UNIV HEIDELBERG,CHILDRENS HOSP,D-6900 HEIDELBERG,GERMANY.
    Activation of DNAse X - A new candidate enzyme mediating DNA fragmentation during apoptosis.1996Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 88, nr 10, s. 266-266Artikkel i tidsskrift (Fagfellevurdert)
  • 34.
    Los, Marek Jan
    et al.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Herr, I.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Friesen, C.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Fulda, S.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Schulze-Osthoff, K.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Debatin, K. M.
    Hematology/Oncology, University Children's Hospital, and the Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; and the Institute of Biochemistry, University of Freiburg, Freiburg, Germany. .
    Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases)1997Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 90, nr 8, s. 3118-3129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system, After drug treatment, a strong increase of caspase activity was found that preceded cell death, Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin, The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis, Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells. (C) 1997 by The American Society of Hematology.

  • 35.
    Lourda, Magda
    et al.
    Karolinska Institute, Sweden.
    Olsson-Akefeldt, Selma
    Karolinska Institute, Sweden.
    Gavhed, Desiree
    Karolinska Institute, Sweden.
    Axdorph Nygell, Ulla
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Berlin, Gösta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Laurencikas, Evaldas
    Karolinska Institute, Sweden.
    von Bahr Greenwood, Tatiana
    Karolinska Institute, Sweden.
    Svensson, Mattias
    Karolinska Institute, Sweden.
    Henter, Jan-Inge
    Karolinska Institute, Sweden.
    Adsorptive depletion of blood monocytes reduces the levels of circulating interleukin-17A in Langerhans cell histiocytosis2016Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, nr 9, s. 1302-1305Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 36. Lundin, J
    et al.
    Hagberg, H
    Repp, R
    Cavallin-Stahl, E
    Freden, S
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Rosenblad, E
    Tjonnfjord, G
    Wiklund, T
    Osterborg, A
    Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome2003Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 101, nr 11, s. 4267-4272Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This phase 2 study evaluated the safety and efficacy of alemtuzumab in 22 patients with advanced mycosis fungoides/Sezary syndrome (MF/SS). Most patients had stage III or IV disease, reduced performance status, and severe itching. The overall response (OR) rate was 55%, with 32% of patients in complete remission (CR) and M in, partial remission (PR). Sezary cells were cleared from the blood in 6 of 7 (86%) patients, and CR in lymph nodes was observed in 6 of 11 (55%) patients. The effect was better on erythro-derma (OR, 69%) than on plaque or skin tumors (OR, 40%) and in patients who had received 1 to 2 previous regimens (OR, 80%) thin in those who had received 3 or more prior regimens (OR, 33%). Itching, self-assessed on a 0 to 10 visual analog scale, was reduced from a median of 8 before treatment to 2 at end. of therapy. Median time to treatment failure was 12 months (range, 5-32+ months). Cytomegalovirus (CMV), reactivation (causing fever without pneumonitis and responding to ganciclovir) occurred in 4 (18%) patients. Six additional patients had suspect or manifest infection (fever of unknown origin, 3, generalized herpes simplex, 1, fatal aspergillosis, 1). One patient had fatal Mycobacterium pneumonia at 10+ months. All serious infectious adverse events (except CMV) occurred in patients who had received 3 or more prior regimens. Progression of squamous cell skin carcinoma was noted in 1 patient. Alemtuzumab shows promising clinical activity and an acceptable safety profile in patients with advanced MF/SS, particularly in patients with erythroderma and severe itching and those who were not heavily pretreated. (C) 2003 by The American Society of Hematology.

  • 37.
    Magnusson, Mattias
    et al.
    Lund University Hospital.
    Brun, Ann CM
    Lund University Hospital.
    Miyake, Noriko
    Lund University Hospital.
    Larsson, Jonas
    Lund University Hospital.
    Ehinger, Mats
    Lund University Hospital.
    Bjornsson, Jon Mar
    Lund University Hospital.
    Wutz, Anton
    Whitehead Institute for Biomedical Research.
    Sigvardsson, Mikael
    Lund University Hospital.
    Karlsson, Stefan
    Lund University Hospital.
    HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development2007Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, nr 9, s. 3687-3696Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Homeobox (Hox) transcription factors are important regulators of normal and malignant hematopoiesis because they control proliferation, differentiation, and self-renewal of hematopoietic cells at different levels of the hematopoietic hierarchy. In transgenic mice we show that the expression of HOXA10 is tightly regulated by doxycycline. Intermediate concentrations of HOXA10 induced a 15-fold increase in the repopulating capacity of hematopoietic stem cells (HSCs) after 13 days of in vitro culture. Notably, the proliferation induction of HSC by HOXA10 was dependent on the HOXA10 concentration, because high levels of HOXA10 had no effect on HSC proliferation. Furthermore, high levels of HOXA10 blocked erythroid and megakaryocyte development, demonstrating that tight regulation of HOXA10 is critical for normal development of the erythroid and megakaryocytic lineages. The HOXA10-mediated effects on hematopoietic cells were associated with altered expression of genes that govern stem-cell self-renewal and lineage commitment (eg, hepatic leukemia factor [HlF], Dickkopf-1 [Dkk-1], growth factor independent-1 [Gfi-1], and Gata-1). Interestingly, binding sites for HOXA10 were found in HLF, Dkk-1, and Gata-1, and Dkk-1 and Gfi-1 were transcriptionally activated by HOXA10. These findings reveal novel molecular pathways that act downstream of HOXA10 and identify HOXA10 as a master regulator of postnatal hematopoietic development.

  • 38.
    Mao, Yumeng
    et al.
    Karolinska Institute, Sweden.
    van Hoef, Vincent
    Karolinska Institute, Sweden.
    Zhang, Xiaonan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Wennerberg, Erik
    Karolinska Institute, Sweden; Weill Cornell Med, NY USA.
    Lorent, Julie
    Karolinska Institute, Sweden.
    Witt, Kristina
    Karolinska Institute, Sweden.
    Masvidal, Laia
    Karolinska Institute, Sweden.
    Liang, Shuo
    Karolinska Institute, Sweden.
    Murray, Shannon
    Nova Southeastern University, FL USA.
    Larsson, Ola
    Karolinska Institute, Sweden.
    Kiessling, Rolf
    Karolinska Institute, Sweden.
    Lundqvist, Andreas
    Karolinska Institute, Sweden; Nova Southeastern University, FL USA.
    IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells2016Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, nr 11, s. 1475-1489Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor postinfusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK-cell functions following cytokine withdrawal to model postinfusion performance. In contrast to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome-associated messenger RNA (mRNA) revealed not only cytokine-dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15-stimulated NK cells was also observed using a clinically applicable protocol for NK-cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.

  • 39.
    Meeths, Marie
    et al.
    Karolinska Institute.
    Chiang, Samuel C. C.
    Karolinska Institute.
    Wood, Stephanie M.
    Karolinska Institute.
    Entesarian, Miriam
    Karolinska Institute.
    Schlums, Heinrich
    Karolinska Institute.
    Bang, Benedicte
    Karolinska Institute.
    Nordenskjold, Edvard
    Karolinska Institute.
    Bjorklund, Caroline
    Umeå University.
    Jakovljevic, Gordana
    Childrens Clinical Hospital Zagreb.
    Jazbec, Janez
    University of Medical Centre Ljubljana.
    Hasle, Henrik
    Aarhus University Hospital Skejby.
    Holmqvist, Britt-Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Rajic, Ljubica
    University of Zagreb.
    Pfeifer, Susan
    Uppsala University.
    Rosthoj, Steen
    Aarhus University Hospital.
    Sabel, Magnus
    University of Gothenburg.
    Salmi, Toivo T.
    Turku University Hospital.
    Stokland, Tore
    University Hospital N Norway.
    Winiarski, Jacek
    Karolinska Institute.
    Ljunggren, Hans-Gustaf
    Karolinska Institute.
    Fadeel, Bengt
    Karolinska Institute.
    Nordenskjold, Magnus
    Karolinska Institute.
    Henter, Jan-Inge
    Karolinska Institutet.
    Bryceson, Yenan T.
    Karolinska Institute.
    Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D2011Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, nr 22, s. 5783-5793Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.

  • 40.
    Mellqvist, Ulf-Henrik
    et al.
    Sahlgrens University Hospital, Sweden .
    Gimsing, Peter
    Rigshosp, Denmark .
    Hjertner, Oyvind
    Norwegian University of Science and Technology, Norway .
    Lenhoff, Stig
    Skåne University Hospital, Sweden .
    Laane, Edward
    North Estonian Regional Hospital, Estonia .
    Remes, Kari
    Turku University, Finland .
    Steingrimsdottir, Hlif
    Landspitali University Hospital, Iceland .
    Abildgaard, Niels
    Odense University Hospital, Denmark .
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Blimark, Cecilie
    Sahlgrens University Hospital, Sweden .
    Dahl, Inger Marie
    University of North Norway, Norway .
    Forsberg, Karin
    Norrlands University Hospital, Sweden .
    Gedde-Dahl, Tobias
    Oslo University Hospital, Norway .
    Gregersen, Henrik
    Aalborg Hospital, Denmark .
    Gruber, Astrid
    Karolinska Institute, Sweden .
    Guldbrandsen, Nina
    Oslo University Hospital, Norway .
    Haukas, Einar
    Stavanger University Hospital, Norway .
    Carlson, Kristina
    Akad University Hospital, Sweden .
    Kvam, Ann Kristin
    Oslo University Hospital, Norway .
    Nahi, Hareth
    Karolinska Institute, Sweden .
    Lindas, Roald
    Haukeland Hospital, Norway .
    Frost Andersen, Niels
    Aarhus University Hospital, Denmark .
    Turesson, Ingemar
    Skåne University Hospital, Sweden .
    Waage, Anders
    Norwegian University of Science and Technology, Norway .
    Westin, Jan
    Sahlgrens University Hospital, Sweden .
    Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, nr 23, s. 4647-4654Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the andgt;= VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

  • 41. Moller, C
    et al.
    Alfredsson, J
    Engström, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Wootz, H
    Xiang, Z
    Lennartsson, J
    Jönsson, Jan-Ingvar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi.
    Nilsson, G
    Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim2005Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 106, nr 4, s. 1330-1336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)-only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEKJMAPK) and phosphatidylinositol 3 (PI3)-kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim(-/-) mast cells. Because apoptosis is abnormally reduced in bim(-/-) mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.

  • 42.
    Månsson, Robert
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Zandi, Sasan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Anderson, Kristina
    Hematopoietic Stem Cell Laboratory Lund University, Sweden.
    Mårtensson, Inga-Lill
    Laboratory of Lymphocyte Signaling and Development The Babraham Institute, Cambridge, United Kingdom.
    Jacobsen, Sten Eirik W.
    Hematopoietic Stem Cell Laboratory Lund University.
    Bryder, David
    Department of Immunology Lund University, Sweden.
    Sigvardsson, Mikael
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi.
    B-lineage commitment prior to surface expression of B220 and CD19 on hematopoietic progenitor cells2008Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 112, nr 4, s. 1048-1055Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Commitment of hematopoietic progenitor cells to B-lymphoid cell fate has been suggested to coincide with the development of PAX5-expressing B220 +CD19+ pro-B cells. We have used a transgenic reporter mouse, expressing human CD25 under the control of the B-lineage- restricted IgII1 (λ5) promoter to investigate the lineage potential of early progenitor cells in the bone marrow. This strategy allowed us to identify a reporter expressing LIN-B220- CD19-CD127 +FLT3+ SCA1lowKITlow population that displays a lack of myeloid and a 90% reduction in in vitro T-cell potential compared with its reporter-negative counterpart. Gene expression analysis demonstrated that these lineage-restricted cells express B- lineage-associated genes to levels comparable with that observed in pro-B cells. These data suggest that B-lineage commitment can occur before the expression of B220 and CD19. © 2008 by The American Society of Hematology.

  • 43.
    Månsson, Robert
    et al.
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Zandi, Sasan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Welinder, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Tsapogas, Panagiotis
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Sakaguchi, Nobuo
    Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
    Bryder, David
    Department for Immunology, Lund University, Lund, Sweden .
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity2010Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 13, s. 2601-2609Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lambda 5 reporter transgenic mice to Rag1-GFP knockin mice. This allowed us to subfractionate common lymphoid progenitors and pre-pro-B (fraction A) cells into lambda 5(-)Rag1(low), lambda 5(-)Rag1(high), and lambda 5(+)Rag1(high) cells. Clonal in vitro differentiation analysis demonstrated that Rag1(low) cells gave rise to B/T and NK cells. Rag1(high) cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells, whereas the lambda 5(+) cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1high populations. These cells also expressed a higher level of the surface protein LY6D, providing an additional tool for the analysis of early lymphoid development. These data suggest that the classic common lymphoid progenitor compartment composes a mixture of cells with relatively restricted lineage potentials, thus opening new possibilities to investigate early hematopoiesis.

  • 44.
    Nagata, Yasunobu
    et al.
    Cleveland Clin, OH 44106 USA.
    Narumi, Satoshi
    Natl Res Inst Child Hlth and Dev, Japan.
    Guan, Yihong
    Cleveland Clin, OH 44106 USA.
    Przychodzen, Bartlomiej P.
    Cleveland Clin, OH 44106 USA.
    Hirsch, Cassandra M.
    Cleveland Clin, OH 44106 USA.
    Makishima, Hideki
    Kyoto Univ, Japan.
    Shima, Hirohito
    Natl Res Inst Child Hlth and Dev, Japan.
    Aly, Mai
    Cleveland Clin, OH 44106 USA; Assiut Univ, Egypt.
    Pastor, Victor
    Univ Freiburg, Germany.
    Kuzmanovic, Teodora
    Cleveland Clin, OH 44106 USA.
    Radivoyevitch, Tomas
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    Adema, Vera
    Cleveland Clin, OH 44106 USA.
    Awada, Hassan
    Cleveland Clin, OH 44106 USA.
    Yoshida, Kenichi
    Kyoto Univ, Japan.
    Li, Samuel
    Case Western Reserve Univ, OH 44106 USA.
    Sole, Francesc
    Univ Autonoma Barcelona, Spain.
    Hanna, Rabi
    Cleveland Clin, OH 44106 USA.
    Jha, Babal K.
    Cleveland Clin, OH 44106 USA.
    LaFramboise, Thomas
    Case Western Reserve Univ, OH 44106 USA.
    Ogawa, Seishi
    Kyoto Univ, Japan.
    Sekeres, Mikkael A.
    Cleveland Clin, OH 44106 USA.
    Wlodarski, Marcin W.
    Univ Freiburg, Germany.
    Cammenga, Jörg
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Maciejewski, Jaroslaw P.
    Cleveland Clin, OH 44106 USA.
    Letter: Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes2018Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132, nr 21, s. 2309-2313Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 45.
    Nilsson, J
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Söderberg, O
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Nilsson, K
    Rosén, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Thioredoxin prolongs survival of B-type chronic lymphocytic leukemia cells2000Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 95, nr 4, s. 1420-1426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thioredoxin (Trx) is a ubiquitous protein disulfide oxidoreductase with antioxidant, cytokine, and chemotactic properties. Previously, we showed that Trx, in synergy with interleukin 1 (IL-1), IL-2, IL-4, tumor necrosis factor a (TNF-a), and CD40-ligation induced S-phase entry and mitosis in normal B cells and B-type chronic lymphocytic leukemia (B-CLL) cells. The viability of B-CLL cells stimulated by these protocols is high, and it has been hypothesized that the overexpression of Bcl-2 found in B-CLL protects the cells from apoptosis in vitro and in vivo. In this study, we have analyzed the response of cells derived from 12 samples of patients with B-CLL to recombinant human Trx in spontaneous apoptosis, with special reference to the Bcl-2 expression. Long-term cultures of B-CLL clones showed significantly higher viability when supplemented with human Trx (P = .031), also exemplified with clones surviving more than 2 months. Short-term cultures of B-CLL cells exposed to 1 ╡g/mL of Trx for 1,5, or 12 days maintained expression or delayed down-regulation of Bcl-2 compared with control cultures containing RPMI 1640 medium and 10% fetal calf serum only (P = .032, .002, .026, respectively). All B-CLL cells expressed constitutive Trx at varying but low levels. In contrast to adult T-cell leukemias, which overexpress Trx, as previously reported. We found that Trx added to B-CLL cells increased in a dose-dependent fashion the release of TNF-a, which has been suggested to be an autocrine growth factor for these cells. In conclusion, we have found that human recombinant Trx induced TNF-a secretion, maintained Bcl-2, and reduced apoptosis in B-CLL cells.

  • 46.
    Nilsson, Lars
    et al.
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Edén, Patrik
    Lund University.
    Olsson, Eleonor
    Lund University.
    Månsson, Robert
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Åstrand-Grundström, Ingbritt
    Lund University.
    Strömbeck, Bodil
    Lund University.
    Theilgaard-Mönch, Kim
    University of Copenhagen.
    Anderson, Kristina
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Hast, Robert
    Karolinska University Hospital.
    Hellström-Lindberg, Eva
    Karolinska University Hospital.
    Samuelsson, Jan
    Karolinska Institute.
    Bergh, Gösta
    Helsingborg Hospital.
    Nerlov, Claus
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Johansson, Bertil
    Lund University.
    Sigvardsson, Mikael
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    Borg, Åke
    Lund University.
    Jacobsen, Sten Eirik W
    Lund Strategic Research Center for Stem Cell Biology and Cell Therapy.
    The molecular signature of MDS stem cells supports a stem-cell origin of 5q-myelodysplastic syndromes2007Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 110, nr 8, s. 3005-3014Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Global gene expression profiling of highly purified 5q-deleted CD34+CD38Thy1+ cells in 5q– myelodysplastic syndromes (MDSs) supported that they might originate from and outcompete normal CD34+CD38Thy1+ hematopoietic stem cells. Few but distinct differences in gene expression distinguished MDS and normal stem cells. Expression of BMI1, encoding a critical regulator of self-renewal, was up-regulated in 5q– stem cells. Whereas multiple previous MDS genetic screens failed to identify altered expression of the gene encoding the myeloid transcription factor CEBPA, stage-specific and extensive down-regulation of CEBPA was specifically observed in MDS progenitors. These studies establish the importance of molecular characterization of distinct stages of cancer stem and progenitor cells to enhance the resolution of stage-specific dysregulated gene expression.

  • 47.
    Nordigården, Amanda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Kraft, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Labi, Verena
    Division of Developmental Immunology, Biocenter, Innsbruck Medical University.
    Lam, Eric W.-F
    Cancer Research-UK Labs, Department of Oncology, Imperial College London, Hammersmith Hospital Campus.
    Villunger, Andreas
    Division of Developmental Immunology, Biocenter, Innsbruck Medical University.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.2009Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, nr 10, s. 2302-2311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.

     

  • 48. Prasad, Mahadesh A. J.
    et al.
    Ungerbäck, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Åhsberg, Josefine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Somasundaram, Rajesh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Strid, Tobias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Larsson, Malin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Mansson, Robert
    Karolinska Institute, Sweden.
    De Paepe, Ayla
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Lilljebjorn, Henrik
    Lund University, Sweden.
    Fioretos, Thoas
    Lund University, Sweden.
    Hagman, James
    National Jewish Heatlh, CO USA.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, nr 26, s. 4052-4059Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia.

  • 49.
    Renz, A.
    et al.
    Department of Immunology and Cell Biology, Department of Hematology/Oncology, University of Münster, D-48149 Münster, Germany, and Department of Radiation Oncology, University of Tübingen, D-72076, Tübingen, Germany..
    Berdel, W. E.
    Department of Immunology and Cell Biology, Department of Hematology/Oncology, University of Münster, D-48149 Münster, Germany, and Department of Radiation Oncology, University of Tübingen, D-72076, Tübingen, Germany..
    Kreuter, M.
    Department of Immunology and Cell Biology, Department of Hematology/Oncology, University of Münster, D-48149 Münster, Germany, and Department of Radiation Oncology, University of Tübingen, D-72076, Tübingen, Germany..
    Belka, C.
    Department of Immunology and Cell Biology, Department of Hematology/Oncology, University of Münster, D-48149 Münster, Germany, and Department of Radiation Oncology, University of Tübingen, D-72076, Tübingen, Germany..
    Schulze-Osthoff, Klaus
    Department of Immunology and Cell Biology, Department of Hematology/Oncology, University of Münster, D-48149 Münster, Germany, and Department of Radiation Oncology, University of Tübingen, D-72076, Tübingen, Germany..
    Los, Marek Jan
    Department of Immunology and Cell Biology, Department of Hematology/Oncology, University of Münster, D-48149 Münster, Germany, and Department of Radiation Oncology, University of Tübingen, D-72076, Tübingen, Germany..
    Rapid extracellular release of cytochrome c is specific for apoptosis and marks cell death in vivo2001Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 98, nr 5, s. 1542-1548Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diverse death stimuli including anticancer drugs trigger apoptosis by inducing the translocation of cytochrome c from the outer mitochondrial compartment into the cytosol. Once released, cytochrome c cooperates with apoptotic protease-activating factor-1 and deoxyadenosine triphosphate in caspase-9 activation and initiation of the apoptotic protease cascade. The results of this study show that on death induction by chemotherapeutic drugs, staurosporine and triggering of the death receptor CD95, cytochrome c not only translocates into the cytosol, but furthermore can be abundantly detected in the extracellular medium. The cytochrome c release from the cell Is a rapid and apoptosis-specific process that occurred within 1 hour after induction of apoptosis, but not during necrosis. Interestingly, elevated cytochrome c levels were observed in sera from patients with hematologic malignancies. In the course of cancer chemo-therapy, the serum levels of cytochrome c in the majority of the patients grew rapidly as a result of increased cell death. These data suggest that monitoring of cytochrome c In the serum of patients with tumors might serve as a useful clinical marker for the detection of the onset of apoptosis and cell turnover in vivo. (C) 2001 by The American Society of Hematology.

  • 50.
    Renz, A.
    et al.
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Comments on the estimation of cell membrane alteration after drug treatment by LDH release - Response2003Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 101, nr 7, s. 2895-2895Artikkel i tidsskrift (Annet vitenskapelig)
12 1 - 50 of 72
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