SRSF2 Mutation in JAK2V617F-Associated MPNs Reduces Polycythemia, Impairs Hematopoietic Progenitor Activity

SFSR2 mutation reduces polycythemia and impairs the activity of hematopoietic stem/progenitor cells in JAK2V617F-associated myeloproliferative neoplasms (MPNs), according to a study published in Blood Cancer Journal. 

Prior research has shown that JAK2V617F is one of the most common somatic mutations associated with MPNs; in turn, SFSR2 mutations are commonly associated with JAK2V617F, especially in myelofibrosis. Nevertheless, the consequences of SRSF2 mutation in JAK2V617F-associated MPNs have yet to be clearly elucidated in existing medical literature.

Researchers conducted a study on Cre-induced SRSF2^P95H/+JAK2^V617F/+ knock-in mice. The research team induced Mx1Cre expression by injecting mice models with 3 doses of polyinosine-polycytosine (pl-pC) at a dose of 300 μg at 4 weeks after birth. This allowed the researchers to identify the impact of SRSF2 mutation on blood parameters and the bone marrow 24 weeks after pl-pC administration (or 28 weeks after birth).

The research team discovered that concurrent SRSF2^P95H and JAK2^V617F mutations resulted in a reduction in the polycythemia phenotype; mice with concurrent mutations demonstrated a significant reduction in erythrocytes, leukocytes, platelets, neutrophils, and hematocrit parameters compared to mice that only had the JAK2^V617F mutation. In addition, mice with concurrent SRSF2^P95H and JAK2^V617F mutations had higher mean corpuscular volume (MCV) volumes compared to JAK2^V617F/+ mice.

Although Jak2^V617F/+ mice demonstrated significant splenomegaly, the investigators found that SRSF2^P95H/+JAK2^V617F/+ mice exhibited reduced spleen size. In addition, whereas JAK2^V617F/+ mice exhibited bone marrow hypercellularity alongside significant increases in erythroid precursors and megakaryocyte clusters, SRSF2^P95H/+JAK2^V617F/+ mice exhibited normal bone marrow cellularity.

The research team found absent/mild bone marrow fibrosis at 24 weeks in both mice groups. They also reported that SRSF2^P95H mutation reduced the competitiveness of hematopoietic stem/progenitor cells; in addition, mice with this mutation had reduced transforming growth factor (TGF)-β levels and increased expressions of S100A8 and S100A9 compared to mice without this mutation; overexpression of S100A8 and S100A9 in turn led to erythroid differentiation defects and myelodysplastic syndrome pathogenesis.

“In conclusion, we demonstrate that SRSF2^P95H mutant reduces development of bone marrow fibrosis in JAK2^V617F-induced MPNs,” the authors of the study wrote in their report. “Additional mutations or genetic abnormalities are required in association with SRSF2^P95H and JAK2^V617F mutations in the development of full-blown myelofibrosis.”

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