RNA splicing factor Rbm25 underlies heterogeneous preleukemic clonal expansion in mice

•Tet2 knockout in mice induces heterogeneous clonal expansion associated with an aberrant expression of RNA splicing factors.•Repression of RNA splicing factor Rbm25 triggers clonal expansion of Tet2 knockout hematopoietic cells in vitro and in vivo. [Display omitted] Clonal expansion sets the stage for cancer genesis by allowing for the accumulation of molecular alterations. Although genetic mutations such as Tet2 that induce clonal expansion and malignancy have been identified, these mutations are also frequently found in healthy individuals. Here, we tracked preleukemic clonal expansion using genetic barcoding in an inducible Tet2 knockout mouse model and found that only a small fraction of hematopoietic stem cells (HSCs) expanded excessively upon Tet2 knockout. These overexpanded HSCs expressed significantly lower levels of genes associated with leukemia and RNA splicing than nonoverexpanded Tet2 knockout HSCs. Knocking down Rbm25, an identified RNA splicing factor, accelerated the expansion of Tet2-knockout hematopoietic cells in vitro and in vivo. Our data suggest that mutations of an epigenetic factor Tet2 induce variability in the expression of an RNA splicing factor Rbm25, which subsequently drives heterogeneous preleukemic clonal expansion. This heterogeneous clonal expansion could contribute to the variable disease risks across individuals. Bramlett and colleagues identify molecular determinants of hematopoietic clonal expansion in response to the mutation of Tet2 by analyzing preleukemic states in an inducible mouse model. Genetic inactivation of Tet2 does not impact hematopoietic clones uniformly, with marked heterogeneity in expansion over time associated with aberrant expression of RNA splicing factors. Repression of RNA splicing factor Rbm25 triggers clonal expansion of Tet2 knockout hematopoietic cells in vitro and in vivo. These data help explain the heterogeneity of outcome observed in patients with TET2-mutated hematopoiesis.