Srsf2 P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice.
Jane Jialu XuAlistair M ChalkMeaghan WallWallace Y LangdonMonique F SmeetsCarl R WalkleyPublished in: Leukemia (2022)
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 Srsf2 P95H/+ mutant model with Tet2 fl/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.
Keyphrases
- bone marrow
- acute myeloid leukemia
- stem cells
- wild type
- endothelial cells
- end stage renal disease
- dendritic cells
- chronic kidney disease
- ejection fraction
- dna methylation
- type diabetes
- gene expression
- signaling pathway
- cell therapy
- prognostic factors
- transcription factor
- genome wide
- peritoneal dialysis
- squamous cell carcinoma
- mesenchymal stem cells
- kidney transplantation
- immune response
- insulin resistance
- skeletal muscle
- adipose tissue
- childhood cancer