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Srsf2P95H initiates myeloid bias and myelodysplastic/myeloproliferative syndrome (MDS/MPN) from hemopoietic stem cells

Monique F. Smeets, Shuh Ying Tan, Jane Jialu Xu, Govardhan Anande, Ashwin Unnikrishnan, Alistair M. Chalk, Scott R. Taylor, John E. Pimanda, Meaghan Wall, Louise E. Purton and Carl R. Walkley

Key points

  • Srsf2P95H/+ mutation within hemopoietic stem cells is required to initiate myeloid biased hemopoiesis.

  • Mutation of Srsf2 is sufficient to initiate the development of MDS/MPN in vivo in the setting of native hemopoiesis.

Abstract

Mutations in SRSF2 occur in myelodysplastic (MDS) and myelodysplastic/myeloproliferative (MDS/MPN) syndromes. SRSF2 mutations cluster at proline 95, with the most frequent a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease and have been identified in age-related clonal hemopoiesis. It is not clear how mutation of SRSF2 modifies hemopoiesis and contributes to the development of myeloid bias and MDS/MPN. Two prior mouse models of Srsf2P95H mutation have been reported, however these models do not recapitulate many of the clinical features of SRSF2 mutant disease and relied on bone marrow transplantation stress to elicit the reported phenotypes. We describe a new conditional murine Srsf2P95H mutation model, where the P95H mutation is expressed physiologically and heterozygously from its endogenous locus after Cre activation. Using multiple Cre lines, we demonstrate that during native hemopoiesis (i.e. no BM transplantation) the Srsf2P95H mutation needs to occur within the hemopoietic stem cell containing populations to promote myelo-monocytic bias and expansion with corresponding transcriptional and RNA splicing changes. When aged, non-transplanted Srsf2P95H animals developed a progressive, transplantable disease characterized by myeloid bias, morphological dysplasia and monocytosis, hallmarks of MDS/MPN in humans. Analysis of co-occurring mutations within the BM demonstrated the acquisition of additional mutations that are recurrent in humans with SRSF2 mutation. The tractable Srsf2P95H/+ knock-in model we have generated is highly relevant to human disease and will serve to elucidate the effect of SRSF2 mutation on initiation and maintenance of MDS/MPN.

  • Submitted April 16, 2018.
  • Accepted June 9, 2018.