Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness

The DNA methylation regulators DNMT3A and TET2 are recurrently mutated in hematological disorders. Despite possessing antagonistic biochemical activities, loss-of-function murine models show overlapping phenotypes in terms of increased hematopoietic stem cell (HSC) fitness. Here, we directly compared the effects of these mutations on hematopoietic progenitor function and disease initiation. In contrast to Dnmt3a-null HSCs, which possess limitless self-renewal in vivo, Tet2-null HSCs unexpectedly exhaust at the same rate as control HSCs in serial transplantation assays despite an initial increase in self-renewal. Moreover, loss of Tet2 more acutely sensitizes hematopoietic cells to the addition of a common co-operating mutation (Flt3ITD) than loss of Dnmt3a, which is associated with a more rapid expansion of committed progenitor cells. The effect of Tet2 mutation manifests more profound myeloid lineage skewing in committed hematopoietic progenitor cells rather than long-term HSCs. Molecular characterization revealed divergent transcriptomes and chromatin accessibility underlying these functional differences. •Tet2-null HSCs exhaust at the same rate as wild-type HSCs in serial transplantation•Loss of Tet2 sensitizes cells to Flt3ITD mutation more dramatically than Dnmt3a•Loss of Dnmt3a permits epigenetic plasticity between hematopoietic progenitors•Tet2 deficiency manifests profound myeloid lineage skewing in progenitor cells Challen and colleagues show that Dnmt3a and Tet2 loss-of-function mutations manifest distinct molecular and functional consequences in different hematopoietic stem and progenitor cell compartments. Despite producing superficially similar phenotypes in terms of stem cell function and disease initiation, we show here divergent influences on progenitor cell lineage skewing, stem cell self-renewal, and predisposition to malignant transformation.