2012年8月28日 訊 /生物谷BIOON/ --英國醫(yī)學研究理事會（MRC）分子生物學實驗室的科學家們已經(jīng)發(fā)現(xiàn),，人體內(nèi)骨髓中的造血干細胞對酒精的主要分解產(chǎn)物是極為敏感的，這可能導致造血干細胞不可逆的DNA損害,。
相關研究在老鼠身上開展的,，其結果發(fā)表于國際權威雜志Nature上,，新的研究表明這種造血干細胞的DNA損害通常存在兩個重要的控制機制：一種可以清除有毒分解產(chǎn)物（乙醛）的酶，一組能夠識別和修復受損DNA的蛋白,。缺乏這兩種保護機制的小鼠由于血液干細胞閉塞導致骨髓造血功能衰竭,。調(diào)查結果提供了一個解釋，為什么有的人患有一種稱為范可尼貧血（FA）的罕見遺傳性疾病,?；加羞@種疾病的人繼承一個或多個FA基因突變，從而導致乙醛引起的DNA損傷得不到修復,。因此,，F(xiàn)A患者患發(fā)育缺陷、骨髓造血功能衰竭,、血液和其他癌癥的風險極高,。這些人缺乏酶ALDH2來消除有毒的乙醛，因此可能對DNA的損傷異常敏感,。作者認為,，酒精消費量可能會導致造血干細胞永久性損壞，骨髓造血功能衰竭和加速老化,，血癌風險增加,。MRC分子生物學實驗室KJ Patel博士說：造血干細胞是給我們的整個生命周期提供了源源不斷的健康的血液細胞，隨著年齡的增長,，這些重要的干細胞變得不那么有效,，因為其DNA受到損傷。我們的研究確定這種DNA損傷的一個重要來源,，定義了干細胞用于對付這種威脅的兩種保護機制,。
研究人員去年發(fā)表的一篇論文顯示，如果沒有這兩個層次的保護,，酒精的分解產(chǎn)物對血液老說是非常有毒的,，我們現(xiàn)在確定了究竟在何處發(fā)生了這種DNA損傷，這一點是非常重要的,，因為這意味著，我們證實了酒精不只是殺害良性循環(huán)細胞,，還能破壞血細胞工廠的造血干細胞,。一旦這些血液干細胞被損壞,，這有可能導致白血病，當血液干細胞都受損傷時將會導致骨髓造血功能衰竭,。這一發(fā)現(xiàn)對廣大自亞洲國家如中國的人來說具有重要意義,，上述地區(qū)的人有多達三分之一的人缺乏ALDH2酶。（生物谷：Bioon.com）
doi:10.1038/nature11368
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Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
Juan I. GaraycoecheaGerry P. CrossanFrederic LangevinMaria DalyMark J. ArendsKetan J. Patel
Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA1, 2, 3. However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes4, 5. Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway (Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol—an exogenous source of acetaldehyde4. Here we report that aged Aldh2−/− Fancd2−/− mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.
