JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
33667305
PubMed Central
PMC8103999
DOI
10.1182/blood.2020005563
PII: S0006-4971(21)00424-9
Knihovny.cz E-zdroje
- MeSH
- bodová mutace účinky léků MeSH
- genový knockin MeSH
- hematopoetické kmenové buňky cytologie metabolismus MeSH
- interferon alfa terapeutické užití MeSH
- Janus kinasa 2 genetika MeSH
- lidé MeSH
- megakaryocyty cytologie metabolismus MeSH
- myeloproliferativní poruchy farmakoterapie genetika MeSH
- myši transgenní MeSH
- myši MeSH
- trombocytový membránový glykoprotein IIb genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- interferon alfa MeSH
- JAK2 protein, human MeSH Prohlížeč
- Jak2 protein, mouse MeSH Prohlížeč
- Janus kinasa 2 MeSH
- trombocytový membránový glykoprotein IIb MeSH
We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41hi) and showed bias for differentiation toward megakaryocytes (Mks). Mouse models of myeloproliferative neoplasms (MPNs) expressing JAK2-V617F (VF) displayed increased frequencies and percentages of the CD41hi vs CD41lo HSCs compared with wild-type controls. An increase in CD41hi HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from patients with MPN. CD41hi HSCs produced a higher number of Mk-colonies of HSCs in single-cell cultures in vitro, but showed reduced long-term reconstitution potential compared with CD41lo HSCs in competitive transplantations in vivo. RNA expression profiling showed an upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41hi HSCs, whereas CD41lo HSCs showed higher gene expression of interferon and the JAK/STAT and TNFα/NFκB signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41hi HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in patients with MPN. Treatment with interferon-α further increased the frequency and percentage of CD41hi HSCs and reduced the number of JAK2-V617F+ HSCs in mice and patients with MPN. The shift toward the CD41hi subset of HSCs by interferon-α provides a possible mechanism of how interferon-α preferentially targets the JAK2 mutant clone.
Department of Biology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic
Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland; and
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Yamamoto R, Morita Y, Ooehara J, et al. . Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell. 2013;154(5):1112-1126. PubMed
Sanjuan-Pla A, Macaulay IC, Jensen CT, et al. . Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature. 2013;502(7470):232-236. PubMed
Gekas C, Graf T. CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age. Blood. 2013;121(22):4463-4472. PubMed
Haas S, Hansson J, Klimmeck D, et al. . Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors. Cell Stem Cell. 2015;17(4):422-434. PubMed
Nishikii H, Kanazawa Y, Umemoto T, et al. . Unipotent Megakaryopoietic Pathway Bridging Hematopoietic Stem Cells and Mature Megakaryocytes. Stem Cells. 2015;33(7):2196-2207. PubMed PMC
Rodriguez-Fraticelli AE, Wolock SL, Weinreb CS, et al. . Clonal analysis of lineage fate in native haematopoiesis. Nature. 2018;553(7687):212-216. PubMed PMC
Shin JY, Hu W, Naramura M, Park CY. High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias. J Exp Med. 2014;211(2):217-231. PubMed PMC
Grinenko T, Arndt K, Portz M, et al. . Clonal expansion capacity defines two consecutive developmental stages of long-term hematopoietic stem cells. J Exp Med. 2014;211(2):209-215. PubMed PMC
Kent DG, Copley MR, Benz C, et al. . Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential. Blood. 2009;113(25):6342-6350. PubMed
Gur-Cohen S, Itkin T, Chakrabarty S, et al. . PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells [published correction appears in Nat Med. 2016 Apr;22(4):446]. Nat Med. 2015;21(11):1307-1317. PubMed PMC
Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667-679. PubMed
Arber DA, Orazi A, Hasserjian R, et al. . The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. PubMed
Bellosillo B, Martínez-Avilés L, Gimeno E, et al. . A higher JAK2 V617F-mutated clone is observed in platelets than in granulocytes from essential thrombocythemia patients, but not in patients with polycythemia vera and primary myelofibrosis. Leukemia. 2007;21(6):1331-1332. PubMed
Li S, Kralovics R, De Libero G, Theocharides A, Gisslinger H, Skoda RC. Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood. 2008;111(7):3863-3866. PubMed
Lundberg P, Takizawa H, Kubovcakova L, et al. . Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F. J Exp Med. 2014;211(11):2213-2230. PubMed PMC
Kiladjian JJ. Long-term treatment with interferon alfa for myeloproliferative neoplasms. Lancet Haematol. 2017;4(4):e150-e151. PubMed
Essers MA, Offner S, Blanco-Bose WE, et al. . IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;458(7240):904-908. PubMed
Tiedt R, Hao-Shen H, Sobas MA, et al. . Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931-3940. PubMed
Hasan S, Lacout C, Marty C, et al. . JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα. Blood. 2013;122(8):1464-1477. PubMed
Grisouard J, Li S, Kubovcakova L, et al. . JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis. Blood. 2016;128(6):839-851. PubMed
Schaefer BC, Schaefer ML, Kappler JW, Marrack P, Kedl RM. Observation of antigen-dependent CD8+ T-cell/ dendritic cell interactions in vivo. Cell Immunol. 2001;214(2):110-122. PubMed
Müller U, Steinhoff U, Reis LF, et al. . Functional role of type I and type II interferons in antiviral defense. Science. 1994;264(5167):1918-1921. PubMed
Mansier O, Kilani B, Guitart AV, et al. . Description of a knock-in mouse model of JAK2V617F MPN emerging from a minority of mutated hematopoietic stem cells. Blood. 2019;134(26):2383-2387. PubMed
Rodgers JT, King KY, Brett JO, et al. . mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature. 2014;510(7505):393-396. PubMed PMC
Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 2010;465(7299):793-797. PubMed PMC
Pietras EM, Lakshminarasimhan R, Techner JM, et al. . Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J Exp Med. 2014;211(2):245-262. PubMed PMC
Mullally A, Bruedigam C, Poveromo L, et al. . Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera. Blood. 2013;121(18):3692-3702. PubMed PMC
Dumont FJ, Coker LZ. Interferon-alpha/beta enhances the expression of Ly-6 antigens on T cells in vivo and in vitro. Eur J Immunol. 1986;16(7):735-740. PubMed
Yokota T, Oritani K, Butz S, et al. . The endothelial antigen ESAM marks primitive hematopoietic progenitors throughout life in mice. Blood. 2009;113(13):2914-2923. PubMed PMC
Ooi AG, Karsunky H, Majeti R, et al. . The adhesion molecule esam1 is a novel hematopoietic stem cell marker. Stem Cells. 2009;27(3):653-661. PubMed PMC
Zheng L, Li MP, Gou ZP, et al. . A pharmacokinetic and pharmacodynamic comparison of a novel pegylated recombinant consensus interferon-α variant with peginterferon-α-2a in healthy subjects. Br J Clin Pharmacol. 2015;79(4):650-659. PubMed PMC
Nakamura-Ishizu A, Matsumura T, Stumpf PS, et al. . Thrombopoietin Metabolically Primes Hematopoietic Stem Cells to Megakaryocyte-Lineage Differentiation. Cell Rep. 2018;25(7):1772-1785 e1776. PubMed
Rao TN, Hansen N, Hilfiker J, et al. . JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative ne oplasms. Blood. 2019;134(21):1832-1846. PubMed PMC
Baumeister J, Chatain N, Hubrich A, et al. . Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms. Leukemia. 2020;34(4):1062-1074. PubMed
Roch A, Trachsel V, Lutolf MP. Brief Report: Single-Cell Analysis Reveals Cell Division-Independent Emergence of Megakaryocytes From Phenotypic Hematopoietic Stem Cells. Stem Cells. 2015;33(10):3152-3157. PubMed
Walter D, Lier A, Geiselhart A, et al. . Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature. 2015;520(7548):549-552. PubMed
Austin RJ, Straube J, Bruedigam C, et al. . Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations. Leukemia. 2020;34(4):1075-1089. PubMed PMC
Ulloa L, Doody J, Massagué J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature. 1999;397(6721):710-713. PubMed
Prendergast AM, Kuck A, van Essen M, Haas S, Blaszkiewicz S, Essers MA. IFNα-mediated remodeling of endothelial cells in the bone marrow niche. Haematologica. 2017;102(3):445-453. PubMed PMC