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Sigvardsson, Mikael
Alternative names
Publications (10 of 90) Show all publications
Dolinska, M., Cai, H., Mansson, A., Shen, J., Xiao, P., Bouderlique, T., . . . Qian, H. (2023). Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option. Blood, 142(1), 73-89
Open this publication in new window or tab >>Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
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2023 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 142, no 1, p. 73-89Article in journal (Refereed) Published
Abstract [en]

Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.

Place, publisher, year, edition, pages
American Society of Hematology, 2023
National Category
Hematology
Identifiers
urn:nbn:se:liu:diva-200817 (URN)10.1182/blood.2022016896 (DOI)001159707400001 ()37018663 (PubMedID)
Note

Funding: Institute for Regenerative Medicine, Karolinska Institute Doctoral Edu-cation (KID) [2-1293/2014, 2021-00480]; Stiftelsen Clas Gro-schinskys Minnesfond [M16 50]; Knut and Alice Wallenberg Foundation [KAW 2020.0102]; Cancer Research KI; Incyte Biosciences Nordic; Blodcancerfonden; Nordic Cancer Union and Cancer Foundation Finland

Available from: 2024-02-08 Created: 2024-02-08 Last updated: 2024-02-23
Sigvardsson, M. (2023). Transcription factor networks link B-lymphocyte development and malignant transformation in leukemia. Genes & Development, 37(15-16), 703-723
Open this publication in new window or tab >>Transcription factor networks link B-lymphocyte development and malignant transformation in leukemia
2023 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 37, no 15-16, p. 703-723Article, review/survey (Refereed) Published
Abstract [en]

Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic leukemia (B-ALL). This disease is manifested as a severe defect in the production of normal blood cells due to the uncontrolled expansion of transformed B-lymphocyte progenitors in the bone marrow. Even though classical genetics identified translocations of transcription factor-coding genes in B-ALL, the extent of the targeting of regulatory networks in malignant transformation was not evident until the emergence of large-scale genomic analyses. There is now evidence that many B-ALL cases present with mutations in genes that encode transcription factors with critical roles in normal B-lymphocyte development. These include PAX5, IKZF1, EBF1, and TCF3, all of which are targeted by translocations or, more commonly, partial inactivation in cases of B-ALL. Even though there is support for the notion that germline polymorphisms in the PAX5 and IKZF1 genes predispose for B-ALL, the majority of leukemias present with somatic mutations in transcription factor-encoding genes. These genetic aberrations are often found in combination with mutations in genes that encode components of the pre-B-cell receptor or the IL-7/TSLP signaling pathways, all of which are important for early B-cell development. This review provides an overview of our current understanding of the molecular interplay that occurs between transcription factors and signaling events during normal and malignant B-lymphocyte development.

Place, publisher, year, edition, pages
Cold Spring Harbor Laboratory Press (CSHL), 2023
Keywords
B-ALL; B-lymphocytes; transcription factors
National Category
Hematology
Identifiers
urn:nbn:se:liu:diva-200818 (URN)10.1101/gad.349879.122 (DOI)37673459 (PubMedID)
Funder
Swedish Cancer Society, 20-1153Swedish Childhood Cancer Foundation, 2022-0019Swedish Research Council, 2021-02379
Available from: 2024-02-08 Created: 2024-02-08 Last updated: 2024-02-08
Xiao, P., Dolinska, M., Sandhow, L., Kondo, M., Johansson, A.-S., Bouderlique, T., . . . Qian, H. (2018). Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm. Blood Advances, 2(5), 534-548
Open this publication in new window or tab >>Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm
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2018 (English)In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 2, no 5, p. 534-548Article in journal (Refereed) Published
Abstract [en]

Mutations of signal-induced proliferation-associated gene 1 (SIPA1), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the Sipa1-/- MPN mouse model, we find that Sipa1 deletion causes phenotypic and functional alterations of BM mesenchymal stem and progenitor cells prior to the initiation of the MPN. Importantly, the altered Sipa1-/- BM niche is required for the development of MDS/MPN following transplantation of normal hematopoietic cells. RNA sequencing reveals an enhanced inflammatory cytokine signaling and dysregulated Dicer1, Kitl, Angptl1, Cxcl12, and Thpo in the Sipa1-/- BM cellular niches. Our data suggest that Sipa1 expression in the BM niche is critical for maintaining BM niche homeostasis. Moreover, Sipa1 loss-induced BM niche alterations likely enable evolution of clonal hematopoiesis to the hematological malignancies. Therefore, restoring Sipa1 expression or modulating the altered signaling pathways involved might offer therapeutic potential for MPN.

Place, publisher, year, edition, pages
American Society of Hematology, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-155832 (URN)10.1182/bloodadvances.2017013599 (DOI)000427259100010 ()29514790 (PubMedID)
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2020-12-15
Wong, W. M., Dolinska, M., Sigvardsson, M., Ekblom, M. & Qian, H. (2016). Letter: A novel Lin-CD34+CD38-integrin alpha 2-bipotential megakaryocyte-erythrocyte progenitor population in the human bone marrow in LEUKEMIA, vol 30, issue 6, pp 1399-1402 [Letter to the editor]. Leukemia, 30(6), 1399-1402
Open this publication in new window or tab >>Letter: A novel Lin-CD34+CD38-integrin alpha 2-bipotential megakaryocyte-erythrocyte progenitor population in the human bone marrow in LEUKEMIA, vol 30, issue 6, pp 1399-1402
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2016 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 6, p. 1399-1402Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-130069 (URN)10.1038/leu.2015.300 (DOI)000377492800020 ()26500141 (PubMedID)
Available from: 2016-07-06 Created: 2016-07-06 Last updated: 2017-11-28
Ungerbäck, J., Åhsberg, J., Strid, T., Somasundaram, R. & Sigvardsson, M. (2015). Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors. Journal of Experimental Medicine, 212(7), 1109-1123
Open this publication in new window or tab >>Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors
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2015 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 7, p. 1109-1123Article in journal (Refereed) Published
Abstract [en]

To investigate how transcription factor levels impact B-lymphocyte development, we generated mice carrying transheterozygous mutations in the Pax5 and Ebf1 genes. Whereas combined reduction of Pax5 and Ebf1 had minimal impact on the development of the earliest CD19(+) progenitors, these cells displayed an increased T cell potential in vivo and in vitro. The alteration in lineage fate depended on a Notch1-mediated conversion process, whereas no signs of de-differentiation could be detected. The differences in functional response to Notch signaling in Wt and Pax5(+/-) Ebf1(+/-) pro-B cells were reflected in the transcriptional response. Both genotypes responded by the generation of intracellular Notch1 and activation of a set of target genes, but only the Pax5(+/-) Ebf1(+/-) pro-B cells down-regulated genes central for the preservation of stable B cell identity. This report stresses the importance of the levels of transcription factor expression during lymphocyte development, and suggests that Pax5 and Ebf1 collaborate to modulate the transcriptional response to Notch signaling. This provides an insight on how transcription factors like Ebf1 and Pax5 preserve cellular identity during differentiation.

Place, publisher, year, edition, pages
Rockefeller University Press, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120223 (URN)10.1084/jem.20132100 (DOI)000357117200012 ()26056231 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; Swedish Childhood cancer foundation; Knut and Alice Wallenbers Stiftelse; Hematolinne

Available from: 2015-07-21 Created: 2015-07-20 Last updated: 2017-12-04
Prasad, M. A. J., Ungerbäck, J., Åhsberg, J., Somasundaram, R., Strid, T., Larsson, M., . . . Sigvardsson, M. (2015). Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency. Blood, 125(26), 4052-4059
Open this publication in new window or tab >>Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, no 26, p. 4052-4059Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Society of Hematology, 2015
National Category
Clinical Medicine Biological Sciences
Identifiers
urn:nbn:se:liu:diva-120281 (URN)10.1182/blood-2014-12-617282 (DOI)000357284300016 ()25838350 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI081878]

Available from: 2015-07-24 Created: 2015-07-24 Last updated: 2017-12-04
Sigvardsson, M. (2015). Editorial Material: Wipping p53 into subservience in B-cell development in BLOOD, vol 126, issue 5, pp 566-567. Blood, 126(5), 566-567
Open this publication in new window or tab >>Editorial Material: Wipping p53 into subservience in B-cell development in BLOOD, vol 126, issue 5, pp 566-567
2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 5, p. 566-567Article in journal, Editorial material (Other academic) Published
Abstract [en]

In this issue of Blood, Yi et al reveal an important role for the protein phosphatase Wip1 (PPM1D) in the regulation of B-cell homeostasis.(1) Mice deficient in the Wip1 gene display increased apoptosis in the pre-B-cell compartment and a reduction in peripheral B-cell numbers, a phenotype exacerbated with age and upon serial transplantations of bone marrow (BM) cells. 1 Even though Wip1 has the ability to modulate multiple signaling pathways in the cell, the restoration of B-cell numbers upon deletion of the p53 gene(1) suggests that an autoregulatory loop between p53 and Wip1 is of importance to maintain normal production of B lymphocytes.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121139 (URN)10.1182/blood-2015-06-649475 (DOI)000358871900003 ()26228168 (PubMedID)
Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2017-12-04
Reyes, J. L., Wang, A., Fernando, M. R., Graepel, R., Leung, G., van Rooijen, N., . . . McKay, D. M. (2015). Splenic B Cells from Hymenolepis diminuta-Infected Mice Ameliorate Colitis Independent of T Cells and via Cooperation with Macrophages. Journal of Immunology, 194(1), 364-378
Open this publication in new window or tab >>Splenic B Cells from Hymenolepis diminuta-Infected Mice Ameliorate Colitis Independent of T Cells and via Cooperation with Macrophages
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 1, p. 364-378Article in journal (Refereed) Published
Abstract [en]

Helminth parasites provoke multicellular immune responses in their hosts that can suppress concomitant disease. The gut lumen-dwelling tapeworm Hymenolepis diminuta, unlike other parasites assessed as helminth therapy, causes no host tissue damage while potently suppressing murine colitis. With the goal of harnessing the immunomodulatory capacity of infection with H. diminuta, we assessed the putative generation of anti-colitic regulatory B cells following H. diminuta infection. Splenic CD19(+) B cells isolated from mice infected 7 [HdBc(7(d))] and 14(d) (but not 3(d)) previously with H. diminuta and transferred to naive mice significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-, oxazolone-, and dextran-sodium sulfate-induced colitis. Mechanistic studies with the DNBS model, revealed the anti-colitic HdBc(7(d)) was within the follicular B cell population and its phenotype was not dependent on IL-4 or IL-10. The HdBc(7(d)) were not characterized by increased expression of CD1d, CD5, CD23, or IL-10 production, but did spontaneously, and upon LPS plus anti-CD40 stimulation, produce more TGF-beta than CD19(+) B cells from controls. DNBS-induced colitis in RAG1(-/-) mice was inhibited by administration of HdBc(7(d)), indicating a lack of a requirement for T and B cells in the recipient; however, depletion of macrophages in recipient mice abrogated the anti-colitic effect of HdBc(7(d)). Thus, in response to H. diminuta, a putatively unique splenic CD19(+) B cell with a functional immunoregulatory program is generated that promotes the suppression of colitis dominated by TH1, TH2, or TH1-plus-TH2 events, and may do so via the synthesis of TGF-beta and the generation of, or cooperation with, a regulatory macrophage.

Place, publisher, year, edition, pages
American Association of Immunologists, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113569 (URN)10.4049/jimmunol.1400738 (DOI)000346700500039 ()25452561 (PubMedID)
Note

Funding Agencies|Natural Sciences and Engineering Research Council of Canada; Crohns and Colitis Foundation of Canada; Alberta Innovates-Health Solutions; Canadian Institutes for Health Research; Canadian Association of Gastroenterology; Janssen Pharmaceuticals; Canadian Digestive Health Foundation; Host-Parasite Interactions Natural Sciences and Engineering Research Council

Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2017-12-05
Somasundaram, R., Prasad, M. A. J., Ungerbäck, J. & Sigvardsson, M. (2015). Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia. Blood, 126(2), 144-152
Open this publication in new window or tab >>Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia
2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 2, p. 144-152Article, review/survey (Refereed) Published
Abstract [en]

B-lymphocyte development in the bone marrow is controlled by the coordinated action of transcription factors creating regulatory networks ensuring activation of the B-lymphoid program and silencing of alternative cell fates. This process is tightly connected to malignant transformation because B-lineage acute lymphoblastic leukemia cellsdisplay a pronounced block in differentiation resulting in the expansion of immature progenitor cells. Over the last few years, high-resolution analysis of genetic changes in leukemia has revealed that several key regulators of normal B-cell development, including IKZF1, TCF3, EBF1, and PAX5, are genetically altered in a large portion of the human B-lineage acute leukemias. This opens the possibility of directly linking the disrupted development as well as aberrant gene expression patterns in leukemic cells to molecular functions of defined transcription factors in normal cell differentiation. This review article focuses on the roles of transcription factors in early B-cell development and their involvement in the formation of human leukemia.

Place, publisher, year, edition, pages
American Society of Hematology, 2015
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-120875 (URN)10.1182/blood-2014-12-575688 (DOI)000358866400008 ()25990863 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Center grant to Hematolinne in Lund; Knut and Alice Wallenberg Foundation; Swedish Childhood Cancer Foundation; Linkoping University

Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2019-02-01
Wahlestedt, M., Norddahl, G. L., Sten, G., Ugale, A., Micha Frisk, M.-A., Mattsson, R., . . . Bryder, D. (2013). An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood, 121(21), 4257-4264
Open this publication in new window or tab >>An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state
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2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 21, p. 4257-4264Article in journal (Refereed) Published
Abstract [en]

Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. Although it is well established that many of the age-induced changes are intrinsic to HSCs, less is known regarding the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform hematopoiesis via blastocyst complementation. Next, we functionally characterized iPS-derived HSCs in primary chimeras and after the transplantation of re-differentiated HSCs into new hosts, the gold standard to assess HSC function. Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results, therefore, favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging.

Place, publisher, year, edition, pages
American Society of Hematology, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96433 (URN)10.1182/blood-2012-11-469080 (DOI)000321873900007 ()
Note

Funding Agencies|Swedish Cancer Society||Swedish Medical Research Council||Swedish Pediatric Leukemia Foundation, Ingabritt och Arne Lundbergs Forskningsstiftelse||AFA Insurance||

Available from: 2013-08-19 Created: 2013-08-19 Last updated: 2017-12-06
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