Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness
Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness
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DOI：
10.1016/j.stemcr.2020.02.011
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发表时间：
2020-04-14
影响因子：
5.9
通讯作者：
Challen, Grant A.
中科院分区：
文献类型：
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作者：
Ostrander, Elizabeth L.;Kramer, Ashley C.;Challen, Grant A.
DNA甲基化调节剂DNMT 3A和TET 2在血液疾病中反复突变。尽管具有拮抗生物化学活性，但功能丧失的鼠模型在增加的造血干细胞（HSC）适应性方面显示重叠的表型。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。与体内具有无限自我更新的Dnmt 3a-无效HSC相反，Tet 2-无效HSC在连续移植测定中出乎意料地以与对照HSC相同的速率耗尽，尽管自我更新最初增加。此外，Tet 2的丢失比Dnmt 3a的丢失更能使造血细胞对常见的协同突变（Flt 3（ITD））的添加更敏感，Dnmt 3a的丢失与定向祖细胞的更快速扩增相关。Tet 2突变的影响在定向造血祖细胞而不是长期HSC中表现出更深刻的髓系偏斜。分子表征揭示了不同的转录组和染色质的可及性这些功能差异的基础。
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.