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JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality.

ABSTRACT: 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.

SUBMITTER: Rao TN

PROVIDER: S-EPMC8103999 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality.

Rao Tata Nageswara TN Hansen Nils N Stetka Jan J Luque Paz Damien D Kalmer Milena M Hilfiker Julian J Endele Max M Ahmed Nouraiz N Kubovcakova Lucia L Rybarikova Margareta M Hao-Shen Hui H Geier Florian F Beisel Christian C Dirnhofer Stefan S Schroeder Timm T Brümmendorf Tim H TH Wolf Dominik D Koschmieder Steffen S Skoda Radek C RC

Blood 20210401 16

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. ...[more]

PMID: 33667305

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Project description:BackgroundPegylated-interferon alpha (PegINFα) treatment of patients with polycythemia vera (PV) and essential thrombocythemia (ET) has resulted in long-term clinical response, decreased JAK2V617F allelic burden and restoration of polyclonal hematopoiesis. The mechanisms of the beneficial effects of PegINFα are not clear, but available evidence suggests direct suppression of JAK2-mutated clone, induction of dormant stem cells to proliferation, and augmentation of an immune effect against PV and ET clones.MethodsWe analyzed the phenotype and frequency of peripheral blood lymphocytes (PBL) from PegINFα treated patients and compared them to patients treated with hydroxyurea (HU). Samples collected at various time points before and during treatment were analyzed using multicolor flow cytometry.ResultsWe found that PegINFα increased the frequency of peripheral blood CD4+ Foxp3+ regulatory T cells (Treg). Highly suppressive Treg, characterized by co-expression of CD39 and HLA-DR, were also increased in PBL from PegINFα treated patients. We observed an augmentation of cycling CD8+ T cells, NK cells, and of poorly activated CD38+CD8+ T cells. Our results also suggest that PegINFα increased the frequency of PD-1+ CD4+ helper cells and PD-1+ CD4+ Foxp3+ Treg cells. None of these changes were present in HU treated patients. We analyzed the correlation between changes in different T cell populations in the peripheral blood with the changes in JAK2V617F allelic burden in clonal granulocytes. Augmentation of Ki-67+ Treg, HLA-DR+ CD39+ Treg, Helios+ Treg and HLA-DR+ CD38+ CD8+ T cells correlated with an increase in JAK2V617F allelic burden. We also found a positive correlation between PD-1+ Treg and JAK2V617F allelic burden; however, the number of available patients was small (n = 7).ConclusionsWe report marked changes in frequencies of PBL subsets after PegINFα treatment, suggesting an immunomodulatory effect by PegINFα. Generation of a more suppressive immune response, as measured by an increase in highly suppressive Treg and poorly activated CD8+ T cells, correlated with a poor molecular response. In this study, we have not identified changes in the PBL that would indicate the presence of an effective anti-tumor response.Trial registration NCT01259856, December 7. 2010 and NCT01259817, December 6. 2010, Grant #1P01CA108671-O1A2, July 17. 2006, Sponsor: MPDRC/NIH, NCI-2012-00269, January 12. 2011 and NCI-2012-00268, January 12. 2011.

Dataset Information

JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality.

Publications

JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality.

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