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.