Dataset Information

SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm.

ABSTRACT: SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2 mutation in JAK2V617F-driven MPN remains elusive. To investigate the consequences of SRSF2^P95H and JAK2^V617F mutations in MPN, we generated Cre-inducible Srsf2^P95H/+Jak2^V617F/+ knock-in mice. We show that co-expression of Srsf2^P95H mutant reduced red blood cell, neutrophil, and platelet counts, attenuated splenomegaly but did not induce bone marrow fibrosis in Jak2^V617F/+ mice. Furthermore, co-expression of Srsf2^P95H diminished the competitiveness of Jak2^V617F mutant hematopoietic stem/progenitor cells. We found that Srsf2^P95H mutant reduced the TGF-β levels but increased the expression of S100A8 and S100A9 in Jak2^V617F/+ mice. Furthermore, enforced expression of S100A9 in Jak2^V617F/+ mice bone marrow significantly reduced the red blood cell, hemoglobin, and hematocrit levels. Overall, these data suggest that concurrent expression of Srsf2^P95H and Jak2^V617F mutants reduces erythropoiesis but does not promote the development of bone marrow fibrosis in mice.

SUBMITTER: Yang Y

PROVIDER: S-EPMC10682023 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm.

Yang Yue Y Abbas Salar S Sayem Mohammad A MA Dutta Avik A Mohi Golam G

Blood cancer journal 20231127 1

SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2 mutation in JAK2V617F-driven MPN remains elusive. To investigate the consequences of SRSF2P95H and JAK2V617F mutations in MPN, we generated Cre-inducible Srsf2P95H/+Jak2V617F/+ knock-in mice. We show that co-expression of Srsf2P95H mutant reduced red blood cell, neutrophil, a ...[more]

PMID: 38012156

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Project description:JAK2V617F is one of the most common mutations in clonal hematopoiesis of indeterminate potential (CHIP) and a major driver of myeloproliferative neoplasms (MPN). To determine the impact of the low frequency JAK2V617F clone on both the hematopoietic system and the bone marrow (BM) stroma, we developed a traceable murine JAK2V617F MPN model where the disease is induced in unconditioned bone marrow transplantation (BMT) recipients. Whole BMT was performed via a single tail vein injection of 5.0x106 cells into unconditioned C57BL/6 Ptprca CD45.1+ recipient mice using CD45.2+ donor cells carrying JAK2V617F isolated from a Poly I:C inducible MPN-like model. BMT resulted in a PV-like phenotype (elevated hematocrit and leukocytosis) with an average donor cell chimerism in peripheral blood of 2.74%. Eight months after BMT, RNA-seq analysis of whole BM sorted according to CD45.1/CD45.2 expression showed significant upregulation of early erythroblast- and myeloid cell-specific transcripts, as well as downregulation of lymphoid transcripts in donor-derived cells compared to controls. Surprisingly, recipient-derived cells also showed upregulation of myeloid- and erythroblast-related transcripts, indicating a skewing of the non-JAK2V617F carrying recipient hematopoietic system towards an MPN-like phenotype. In addition, RNA-seq analysis of the BM stroma from JAK2V617F BMT recipients 28-32 weeks post-BMT indicated significant loss of osteo-mesenchymal transcripts. Consistently, micro-CT imaging indicated loss of trabecular bone. Our model uncovers the impact of JAK2V617F donor cells on the host BM microenvironment and hematopoietic system, driving an MPN phenotype even with low donor cell chimerism within unconditioned recipients. The observation that BMT recipient’s hematopoietic cells, which do not carry JAK2V617F, acquire unique transcriptomic and phenotypic profiles suggests that the MPN clone not only impacts hematopoiesis-supporting stroma but profoundly influences unmutated cells, challenging our current understanding and therapeutic approaches to MPNs and other CHIP-associated diseases.

Dataset Information

SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm.

Publications

SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm.

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