Physiologic expression of Srsf2(P95H) causes myeloid expansion, impaired competitive stem cell function and initiates the myeloproliferative/myelodysplastic syndrome in vivo [WES]. Mus musculus

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: Whole Exome Sequencing of in vivo tamoxifen treated R26CreERT2 Srsf2 P95H, using Illumina HiSeq X Ten. Exome sequencing data was acquired for 6 samples from 50-60 weeks post tamoxifen treatment (time of euthanasia due to animals becoming moribund). Genomic DNA was isolated from both whole BM and matched ear tissue from three independent animals (two R26-CreERT2 Srsf2P95H/+ and one hScl-CreERT R26eYFP Srsf2P95H/+ ). SRA Study accession: SRP108226. Please note that, for somatic mutation calling, each processed data file was generated from two samples. For the variant calling, there are multiple files per animal+ tissue depending on the method used.