MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Haematology, University of Cambridge, Cambridge, UK.
Mol Cell. 2020 Dec 17;80(6):996-1012.e9. doi: 10.1016/j.molcel.2020.10.012. Epub 2020 Nov 3.
Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.
活性醛类物质是新陈代谢的副产物,通常可被多种酶家族清除。我们发现,缺乏两种醛类解毒酶——线粒体 ALDH2 和细胞质 ADH5 的小鼠寿命大大缩短,并发展为白血病。造血功能受到严重破坏,造血干细胞和共同淋巴祖细胞减少,导致获得性免疫系统严重耗竭。我们表明,甲醛是 ALDH2 和 ADH5 的常见底物,并建立了定量检测组织中血液甲醛和甲醛-DNA 加合物升高的方法。骨髓衍生祖细胞积极参与 DNA 修复,但也会留下类似于与衰老相关的人类癌症突变特征的甲醛驱动的突变特征。此外,我们在导致先前未表征的遗传性骨髓衰竭和白血病前期综合征的儿童中发现了类似的遗传缺陷。因此,内源性甲醛清除本身对于造血和限制体细胞突变至关重要。