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 (Flt3^ITD) 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.

DNA 甲基化调节因子DNMT3A和TET2在血液病中反复发生突变。尽管具有拮抗性生化活性，但功能丧失的小鼠模型在增加的造血干细胞 (HSC) 适应性方面显示出重叠的表型。在这里，我们直接比较了这些突变对造血祖细胞功能和疾病发生的影响。在对比化酶Dnmt3a -null造血干细胞，其具有无限自我更新体内，TET2 -null的HSC意外以相同的速率在连续移植测定控制的HSCs，尽管在自我更新的初始增加排放。此外，Tet2 的损失与Dnmt3a 的缺失相比，Dnmt3a 的缺失使造血细胞对常见协同突变 ( Flt3 ^ITD )的加入更敏感，后者与定向祖细胞的更快速扩增有关。Tet2突变的影响在定型造血祖细胞而不是长期造血干细胞中表现出更严重的骨髓谱​​系偏斜。分子表征揭示了这些功能差异背后的不同转录组和染色质可及性。