Abstract
Recurrent mutations in RNA splicing proteins and epigenetic regulators contribute to the development of myelodysplastic syndrome (MDS) and related myeloid neoplasms. In chronic myelomonocytic leukemia (CMML), SRSF2 mutations occur in ~50% of patients and TET2 mutations in ~60%. Clonal analysis indicates that either mutation can arise as the founder lesion. Based on human cancer genetics we crossed an inducible Srsf2P95H/+ mutant model with Tet2fl/fl mice to mutate both concomitantly in hematopoietic stem cells. At 20–24 weeks post mutation induction, we observed subtle differences in the Srsf2/Tet2 mutants compared to either single mutant. Under conditions of native hematopoiesis with aging, we see a distinct myeloid bias and monocytosis in the Srsf2/Tet2 mutants. A subset of the compound Srsf2/Tet2 mutants display an increased granulocytic and distinctive monocytic proliferation (myelomonocytic hyperplasia), with increased immature promonocytes and monoblasts and binucleate promonocytes. Exome analysis of progressed disease demonstrated mutations in genes and pathways similar to those reported in human CMML. Upon transplantation, recipients developed leukocytosis, monocytosis, and splenomegaly. We reproduce Srsf2/Tet2 co-operativity in vivo, yielding a disease with core characteristics of CMML, unlike single Srsf2 or Tet2 mutation. This model represents a significant step toward building high fidelity and genetically tractable models of CMML.
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Data availability
Raw data are available in the Sequence Read Archive (SRA) submission: PRJNA850841.
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Acknowledgements
The authors would like to thank L. Purton for discussion and comments; St. Vincent’s Hospital BioResources Centre for care of experimental animals; St. Vincent’s Institute Flow Cytometry Core Facility. This work was supported by the Cancer Council of Victoria (CRW, AMC, MW, and WYL; APP1126010), Victorian Cancer Agency Research Fellowship (CRW; MCRF15015); and in part by the Victorian State Government Operational Infrastructure Support (OIS) to St Vincent’s Institute.
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JJX, MFS, and CRW conceptualized the study; JJX, WYL, MFS, and CRW designed the experiments; JJX, AMC, MW, MFS, and CRW performed the experiments.; JJX and AMC produced the figures; JJX wrote the original manuscript; JJX, AMC, MW, WYL, MFS, and CRW reviewed and edited the manuscript; AMC, MW, WYL, and CRW were responsible for funding acquisition; MFS and CRW provided supervision.
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Xu, J.J., Chalk, A.M., Wall, M. et al. Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice. Leukemia 36, 2883–2893 (2022). https://doi.org/10.1038/s41375-022-01727-6
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DOI: https://doi.org/10.1038/s41375-022-01727-6