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

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.