Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia like disease in mice.

Xu, J. J.; Chalk, A. M.; Wall, M.; Langdon, W. Y.; Smeets, M. F.; Walkley, C. R.

doi:10.1101/2022.06.21.496931

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bioRxiv · 10.1101/2022.06.21.496931

Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia like disease in mice.

Xu, J. J.·Chalk, A. M.·Wall, M.·Langdon, W. Y.·Smeets, M. F.·Walkley, C. R.

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Abstract

Recurrent mutations in two pathways - the RNA spliceosome (eg. SRSF2, SF3B1, U2AF1) and epigenetic regulators (eg. DNMT3, TET2) - 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%, representing two of the most frequent mutations in these cancers. Clonal analysis has indicated that either mutation can arise as the founder lesion, however, our understanding of the basis for the co-operativity of these mutations in the evolution of CMML is limited. Based on human cancer genetics we crossed an inducible Srsf2P95H/+ mutant model with Tet2fl/fl mice to mutate both concomitantly (or individually) in hematopoietic stem cells. At 20-24 weeks post gene mutation, 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 (myelo-monocytic hyperplasia), with increased immature promonocytes and monoblasts ([~]10-15% total nucleated cells), and evidence of binucleate promonocytes. Exome analysis of progressed disease demonstrates mutations in genes and pathways similar to those reported in human CMML. Upon transplantation, recipients developed leukocytosis, monocytosis and splenomegaly. This demonstrates we can 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. Key pointsO_LISrsf2P95H/+ co-operates with Tet2-/- to initiate CMML in a murine model C_LIO_LISrsf2P95H and Tet2 null mutations synergize in the development of monocytosis C_LI

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Xu, J. J., Chalk, A. M., Wall, M., Langdon, W. Y., Smeets, M. F., Walkley, C. R.. 2022-06-21. Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia like disease in mice.. https://doi.org/10.1101/2022.06.21.496931

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