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Sigvardsson, Mikael
Publications (10 of 87) Show all publications
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 in journal (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: 2017-12-04
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
Xu, W., Carr, T., Ramirez, K., McGregor, S., Sigvardsson, M. & Kee, B. L. (2013). E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood, 121(9), 1534-1542
Open this publication in new window or tab >>E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment
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2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 9, p. 1534-1542Article in journal (Refereed) Published
Abstract [en]

The E2A transcription factors promote the development of thymus-seeding cells, but it remains unknown whether these proteins play a role in T lymphocyte lineage specification or commitment. Here, we showed that E2A proteins were required to promote T-lymphocyte commitment from DN2 thymocytes and to extinguish their potential for alternative fates. E2A proteins functioned in DN2 cells to limit expression of Gata3, which encodes an essential T-lymphocyte transcription factor whose ectopic expression can arrest T-cell differentiation. Genetic, or small interfering RNA-mediated, reduction of Gata3 rescued T-cell differentiation in the absence of E2A and restricted the development of alternative lineages by limiting the expanded self-renewal potential in E2A(-/-) DN2 cells. Our data support a novel paradigm in lymphocyte lineage commitment in which the E2A proteins are necessary to limit the expression of an essential lineage specification and commitment factor to restrain self-renewal and to prevent an arrest in differentiation.

Place, publisher, year, edition, pages
American Society of Hematology, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-95981 (URN)000321750300015 ()
Note

Funding Agencies|National Institutes of Health|R01 CA099978R01 AI079213R21 AI096530|Leukemia & Lymphoma Society||University of Chicago|T32 GM07281||T32 GM38663||R01 CA099978-S1|

DOI does not work: 10.1182/blood-2012-08-1449447

Available from: 2013-08-12 Created: 2013-08-12 Last updated: 2018-02-27
Åhsberg, J., Ungerbäck, J., Strid, T., Welinder, E., Stjernberg, J., Larsson, M., . . . Sigvardsson, M. (2013). Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner. Journal of Biological Chemistry, 288(46), 33449-33461
Open this publication in new window or tab >>Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, p. 33449-33461Article in journal (Refereed) Published
Abstract [en]

Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2R-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1(+/-) pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2013
Keyword
Development; Differentiation; Immunology; Lymphocyte; Transcription Factors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-103303 (URN)10.1074/jbc.M113.506261 (DOI)000328841700057 ()
Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2017-12-06
Verykokakis, M., Krishnamoorthy, V., Iavarone, A., Lasorella, A., Sigvardsson, M. & Kee, B. L. (2013). Essential Functions for ID Proteins at Multiple Checkpoints in Invariant NKT Cell Development. Journal of Immunology, 191(12), 5973-5983
Open this publication in new window or tab >>Essential Functions for ID Proteins at Multiple Checkpoints in Invariant NKT Cell Development
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2013 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, no 12, p. 5973-5983Article in journal (Refereed) Published
Abstract [en]

Invariant NKT (iNKT) cells display characteristics of both adaptive and innate lymphoid cells (ILCs). Like other ILCs, iNKT cells constitutively express ID proteins, which antagonize the E protein transcription factors that are essential for adaptive lymphocyte development. However, unlike ILCs, ID2 is not essential for thymic iNKT cell development. In this study, we demonstrated that ID2 and ID3 redundantly promoted iNKT cell lineage specification involving the induction of the signature transcription factor PLZF and that ID3 was critical for development of TBET-dependent NKT1 cells. In contrast, both ID2 and ID3 limited iNKT cell numbers by enforcing the postselection checkpoint in conventional thymocytes. Therefore, iNKT cells show both adaptive and innate-like requirements for ID proteins at distinct checkpoints during iNKT cell development.

Place, publisher, year, edition, pages
American Association of Immunologists, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-103291 (URN)10.4049/jimmunol.1301521 (DOI)000328483900024 ()
Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2017-12-06
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