Physiologic expression of Srsf2(P95H) causes myeloid expansion, impaired competitive stem cell function and initiates the myeloproliferative/myelodysplastic syndrome in vivo [RNA-seq]

Mutations in the RNA splicing complex member SRSF2 are found frequently in myelodysplastic syndrome and related malignancies such as chronic myelomonocytic leukemia. These mutations cluster on proline 95, with P95H the most frequent. How SRSF2P95H mutations modify hematopoiesis and promote MDS/MPN development is not clear. We have established a conditionally activatable Srsf2P95H/+ knock-in allele which, when expressed within the hematopoietic stem cell populations caused profound myeloid bias, at the expense of erythroid and lymphoid cells, and a reduced frequency and competitive repopulation of HSCs. Long-term aging of Srsf2P95H/+ resulted in the development of MDS/MPN characterised by myeloid dysplasia and monocytosis. Reproducible key phenotypic features make this a mouse model suitable for mechanistic and preclinical MDS sudies. Overall design: RNAseq of whole bone marrow in vivo tamoxifen treated R26CreERT2 Srsf2 P95H generated by deep sequencing, using Illumina NextSeq500