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Eliasson, Pernilla
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Publications (10 of 10) Show all publications
Halvarsson, C., Eliasson, P. & Jonsson, J.-I. (2012). Hypoxia-inducible factor (HIF)-1alpha is not required for hypoxia-mediated protection of hematopoietic stem cells to oxidative stress-induced cell death in FEBS JOURNAL, vol 279, issue SI, pp 203-203. In: FEBS JOURNAL (pp. 203-203). Wiley-Blackwell, 279(SI)
Open this publication in new window or tab >>Hypoxia-inducible factor (HIF)-1alpha is not required for hypoxia-mediated protection of hematopoietic stem cells to oxidative stress-induced cell death in FEBS JOURNAL, vol 279, issue SI, pp 203-203
2012 (English)In: FEBS JOURNAL, Wiley-Blackwell , 2012, Vol. 279, no SI, p. 203-203Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Series
FEBS JOURNAL, ISSN 1742-464X
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-82053 (URN)000308128601487 ()
Available from: 2012-10-01 Created: 2012-09-28 Last updated: 2012-10-01
Tang, Y.-j., Halvarsson, C., Eliasson, P. & Jönsson, J.-I. (2012). Letter: Hypoxic and normoxic in vitro cultures maintain similar numbers of long-term reconstituting hematopoietic stem cells from mouse bone marrow [Letter to the editor]. Experimental Hematology, 40(11), 879-881
Open this publication in new window or tab >>Letter: Hypoxic and normoxic in vitro cultures maintain similar numbers of long-term reconstituting hematopoietic stem cells from mouse bone marrow
2012 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 40, no 11, p. 879-881Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85627 (URN)10.1016/j.exphem.2012.07.005 (DOI)000310182400001 ()
Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2018-10-18
Nordigården, A., Zetterblad, J., Trinks, C., Green, H., Eliasson, P., Druid, P., . . . Jönsson, J.-I. (2011). Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice. British Journal of Haematology, 155(2), 198-208
Open this publication in new window or tab >>Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice
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2011 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, no 2, p. 198-208Article in journal (Refereed) Published
Abstract [en]

Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

Place, publisher, year, edition, pages
Blackwell Publishing, 2011
Keywords
acute myeloid leukaemia, apoptosis, signalling, drugs, murine model, leukaemia therapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72031 (URN)10.1111/j.1365-2141.2011.08819.x (DOI)000296063400006 ()
Note
Funding Agencies|Swedish Cancer Foundation||Swedish Childrens Cancer Foundation||Swedish Research Council||County Council of Ostergotland||Cancer Foundation of Ostergotland||Ollie and Elof Ericssons Foundation||Available from: 2011-11-11 Created: 2011-11-11 Last updated: 2017-12-08
Eliasson, P., Rehn, M., Hammar, P., Larsson, P., Sirenko, O., A Flippin, L., . . . Jönsson, J.-I. (2010). Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture. Experimental Hematology, 38(4), 301-310
Open this publication in new window or tab >>Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
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2010 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 38, no 4, p. 301-310Article in journal (Refereed) Published
Abstract [en]

Objective. Recent evidence suggests that hematopoietic stem cells (HSCs) in the bone marrow (BM) are located in areas where the environment is hypoxic. Although previous studies have demonstrated positive effects by hypoxia, its role in HSC maintenance has not been fully elucidated, neither has the molecular mechanisms been delineated. Here, we have investigated the consequence of in vitro incubation of HSCs in hypoxia prior to transplantation and analyzed the role of hypoxia-inducible factor (HIF)-1 alpha. Materials and Methods. HSC and progenitor populations isolated from mouse BM were cultured in 20% or 1% O-2, and analyzed for effects on cell cycle, expression of cyclin-dependent kinase inhibitors genes, and reconstituting ability to lethally irradiated mice. The involvement of HIF-1 alpha was studied using methods of protein stabilization and gene silencing. Results. When long-term FLT3(-)CD34(-)Lin(-)Sca-1(+)c-Kit(+) (LSK) cells were cultured in hypoxia, cell numbers were significantly reduced in comparison to normoxia. This was due to a decrease in proliferation and more cells accumulating in G(0). Moreover, the proportion of HSCs with long-term engraftment potential was increased. Whereas expression of the cyclin-dependent kinase inhibitor genes p21(cip1), p27(Kip1), and p57(Kip2) increased in LSK cells by hypoxia, only p21(cip1) was upregulated in FLT3(-)CD34(-)LSK cells. We could demonstrate that expression of p27(KiP1) and p57(Kip2) was dependent of HIF-1 alpha. Surprisingly, overexpression of constitutively active HIF-1 alpha or treatment with the HIF stabilizer agent FG-4497 led to a reduction in HSC reconstituting ability. Conclusions. Our results imply that hypoxia, in part via HIF-1 alpha, maintains HSCs by decreasing proliferation and favoring quiescence.

Place, publisher, year, edition, pages
Elsevier, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54780 (URN)10.1016/j.exphem.2010.01.005 (DOI)000276054300005 ()
Note

Original Publication: Pernilla Eliasson, Matilda Rehn, Petter Hammar, Peter Larsson, Oksana Sirenko, Lee A Flippin, Jorg Cammenga and Jan-Ingvar Jönsson, Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture, 2010, EXPERIMENTAL HEMATOLOGY, (38), 4, 301-310. http://dx.doi.org/10.1016/j.exphem.2010.01.005 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/

On the day of the defence date the title of this article was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.

When finally published online the title of this article changed name to Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.

Available from: 2010-04-09 Created: 2010-04-09 Last updated: 2017-12-12Bibliographically approved
Eliasson, P. & Jönsson, J.-I. (2010). The Hematopoietic Stem Cell Niche: Low in Oxygen but a Nice Place to be. Journal of Cellular Physiology, 222(1), 17-22
Open this publication in new window or tab >>The Hematopoietic Stem Cell Niche: Low in Oxygen but a Nice Place to be
2010 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 222, no 1, p. 17-22Article, review/survey (Refereed) Published
Abstract [en]

The enormous regenerative capacity of the blood system to sustain functionally mature cells are generated from highly proliferative, short-lived progenitors, which in turn arise from a rare population of pluripotent and self-renewing hematopoietic stem cells (HSC). In the bone marrow, these stem cells are kept in a low proliferative, relatively quiescent state in close proximity to stromal cells and osteoblasts, forming specialized niches. The interaction in particular to bone is crucial to prevent exhaustion of HSCs from uncontrolled cell-cycle entry and to excessive proliferation. In addition, the niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. One of the key issues is to identify conditions to increase the number of HSCs, either in vivo or during ex vivo growth cultures. This task has been very difficult to resolve and most attempts have been unsuccessful. However, the mechanistic insights to HSC self-renewal and preservation are gradually increasing and there is now hope that future research will enable scientists and clinicians to modulate the process. In this review, we will focus on the molecular mechanisms of self-renewal and HSC maintenance in the light of novel findings that HSCs reside at the lowest end of an oxygen gradient. Hypoxia appears to regulate hematopoiesis in the bone marrow by maintaining important HSC functions, such as cell cycle control, survival, metabolism, and protection against oxidative stress. To improve the therapeutic expansion of HSCs we need to learn more about the molecular mechanisms of hypoxia-mediated regulation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-52904 (URN)10.1002/jcp.21908 (DOI)
Available from: 2010-01-13 Created: 2010-01-12 Last updated: 2017-12-12
Nordigården, A., Kraft, M., Eliasson, P., Labi, V., Lam, E.-F. W. F., Villunger, A. & Jönsson, J.-I. (2009). 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.. Blood, 113(10), 2302-2311
Open this publication in new window or tab >>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.
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2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 10, p. 2302-2311Article in journal (Refereed) Published
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.

 

Place, publisher, year, edition, pages
Washington, D.C: The American Society of Hematology, 2009
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-52728 (URN)10.1182/blood-2008-07-167023 (DOI)
Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2018-01-12
Eliasson, P. (2009). Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. p. 93
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1160
Keywords
hematopoietic stem cells, hypoxia, self-renewal, survival, acute myeloid leukemia, FLT3
National Category
Biochemistry and Molecular Biology Hematology
Identifiers
urn:nbn:se:liu:diva-52932 (URN)978-91-7393-470-1 (ISBN)
Public defence
2009-12-11, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Note

On the day of the defence date the title of article II was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.

Available from: 2010-01-19 Created: 2010-01-13 Last updated: 2018-09-11Bibliographically approved
Eliasson, P., Karlsson, R. & Jönsson, J.-I. (2006). Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability. Journal of Stem Cells, 1(4), 247-257
Open this publication in new window or tab >>Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
2006 (English)In: Journal of Stem Cells, ISSN 1556-8539, Vol. 1, no 4, p. 247-257Article in journal (Refereed) Published
Abstract [en]

Self-renewal is a prerequisite for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow throughout adult life. Cytokines are mainly providing pro-survival signals of HSC, whereas low oxygen levels (hypoxia) were recently shown to influence self-renewal. In contrast, the effects on other progenitor cell types is not clear. In the present work, we have analyzed whether hypoxia has any effects on mouse multipotent progenitors. When bone marrow-derived Lin-Sca1+c-kit+ (LSK) cells were kept in hypoxic cultures (1% O2 ) for 4 days together with cytokines, the numbers of colony forming high-proliferative progenitors (HPP-CFC) and precursors for cobble-stone forming cells (CAFC) were increased compared to normoxic conditions. A similar effect was seen with pre-CFCmulti from unfractionated bone marrow, whereas more committed progenitors (CFU-GM) were expanded better in normoxia compared to hypoxia. The observed increase in numbers of primitive colony-forming progenitor cells was associated with maintenance of the c-kit/Sca-1 phenotype and a preferential expansion of immature  blast-like appearing cells. The results suggest that a major function of hypoxia is to regulate differentiation by increased self-renewal. Furthermore, in cultures of limited cytokine supply, survival of the stem cell-like cell line FDCP-mix was increased during hypoxia. Thus, hypoxia allows for better survival and self-renewal of multipotent progenitors and HSCs from adult bone marrow. Such culture conditions may have beneficial clinical implications for ex vivo purposes and may improve the yields of stem cells and early progenitors.

Place, publisher, year, edition, pages
Nova Science Publishers, Inc., 2006
Keywords
Hematopoiesis, Stem cells, Progenitor, Hypoxia, Survival, Self-renewal
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17713 (URN)
Note

Original Publication: Pernilla Eliasson, Richard Karlsson and Jan-Ingvar Jönsson, Hypoxia Expands Primitive Hematopoietic Progenitor Cellsfrom Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability, 2006, Journal of Stem Cells, (1), 4, 247-257. https://www.novapublishers.com/catalog/editorial.php?products_id=3730 Copyright: Nova Science Publishers https://www.novapublishers.com/

Available from: 2009-04-16 Created: 2009-04-16 Last updated: 2018-05-29Bibliographically approved
Eliasson, P., Andersson, P., Willander, K., Linderholm, M., Söderkvist, P. & Jönsson, J.-I. (2006). Letter: Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia [Letter to the editor]. European Journal of Haematology, 77(1), 86-87
Open this publication in new window or tab >>Letter: Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia
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2006 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 77, no 1, p. 86-87Article in journal, Letter (Other academic) Published
Abstract [en]

[No abstract available]

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37786 (URN)10.1111/j.0902-4441.2006.t01-1-EJH2605.x (DOI)38625 (Local ID)38625 (Archive number)38625 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
Eliasson, P., Widegren, E. & Jönsson, J.-I. Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability.
Open this publication in new window or tab >>Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.

Keywords
Hematopoiesis, Stem cells, Progenitor, Hypoxia, Hypoxia-inducible factor 1 alpha, oxidative stress, Puruvate dehydrogenase kinase 1
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-52941 (URN)
Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2018-10-08
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