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

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.