Epigenetic modifying enzymes DNMT3A and TET2 are recurrently mutated in hematological disorders despite possessing opposing biochemical functions in the DNA methylation processes. Using conditional ablation, we show these contrasting genotypes result in different functional effects in hematopoietic stem cells (HSCs). Loss of Dnmt3a bestows enhanced self-renewal on HSCs in serial, competitive repopulation assays while Tet2 loss functionally depletes HSCs after a tertiary transplant despite an initial competitive advantage. Moreover, loss of Tet2 sensitizes HSCs to the addition of a common leukemic driver mutation Flt3-ITD. Tet2-null mice experience a 5-fold decrease in median survival time when combined with Flt3-ITD while that of Dnmt3a-null mice decreases 1.5-fold. Molecular characterization of transcriptomes and chromatin accessibility reflects the functional differences between the genotypes as Dnmt3a-null cells reside in a more stem cell-like state while Tet2 loss leads to functional attrition of down-stream progenitors. These data further prove that DNMT3A and TET2 mutations lead HSCs down different molecular and functional pathways despite similar disease destinations. SOURCE: Grant,A,Challen (gchallen@DOM.wustl.edu) -  Washington University School of Medicine

Pluto Bioinformatics

GSE139911: DNMT3A and TET2 Mutations Increase Hematopoietic Stem Cell Fitness Through Distinct Mechanisms