2012年8月28日 訊 /生物谷BIOON/ --英國(guó)醫(yī)學(xué)研究理事會(huì)（MRC）分子生物學(xué)實(shí)驗(yàn)室的科學(xué)家們已經(jīng)發(fā)現(xiàn),，人體內(nèi)骨髓中的造血干細(xì)胞對(duì)酒精的主要分解產(chǎn)物是極為敏感的，這可能導(dǎo)致造血干細(xì)胞不可逆的DNA損害,。
相關(guān)研究在老鼠身上開(kāi)展的,，其結(jié)果發(fā)表于國(guó)際權(quán)威雜志Nature上,，新的研究表明這種造血干細(xì)胞的DNA損害通常存在兩個(gè)重要的控制機(jī)制：一種可以清除有毒分解產(chǎn)物（乙醛）的酶,，一組能夠識(shí)別和修復(fù)受損DNA的蛋白。缺乏這兩種保護(hù)機(jī)制的小鼠由于血液干細(xì)胞閉塞導(dǎo)致骨髓造血功能衰竭,。調(diào)查結(jié)果提供了一個(gè)解釋?zhuān)瑸槭裁从械娜嘶加幸环N稱(chēng)為范可尼貧血（FA）的罕見(jiàn)遺傳性疾病?；加羞@種疾病的人繼承一個(gè)或多個(gè)FA基因突變,，從而導(dǎo)致乙醛引起的DNA損傷得不到修復(fù)。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(fēng)險(xiǎn)極高,。這些人缺乏酶ALDH2來(lái)消除有毒的乙醛,，因此可能對(duì)DNA的損傷異常敏感。作者認(rèn)為,，酒精消費(fèi)量可能會(huì)導(dǎo)致造血干細(xì)胞永久性損壞,，骨髓造血功能衰竭和加速老化，血癌風(fēng)險(xiǎn)增加,。MRC分子生物學(xué)實(shí)驗(yàn)室KJ Patel博士說(shuō)：造血干細(xì)胞是給我們的整個(gè)生命周期提供了源源不斷的健康的血液細(xì)胞,，隨著年齡的增長(zhǎng)，這些重要的干細(xì)胞變得不那么有效,，因?yàn)槠銬NA受到損傷,。我們的研究確定這種DNA損傷的一個(gè)重要來(lái)源，定義了干細(xì)胞用于對(duì)付這種威脅的兩種保護(hù)機(jī)制,。
研究人員去年發(fā)表的一篇論文顯示,，如果沒(méi)有這兩個(gè)層次的保護(hù)，酒精的分解產(chǎn)物對(duì)血液老說(shuō)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(diǎn)是非常重要的，因?yàn)檫@意味著,，我們證實(shí)了酒精不只是殺害良性循環(huán)細(xì)胞,，還能破壞血細(xì)胞工廠(chǎng)的造血干細(xì)胞。一旦這些血液干細(xì)胞被損壞,，這有可能導(dǎo)致白血病,，當(dāng)血液干細(xì)胞都受損傷時(shí)將會(huì)導(dǎo)致骨髓造血功能衰竭。這一發(fā)現(xiàn)對(duì)廣大自亞洲國(guó)家如中國(guó)的人來(lái)說(shuō)具有重要意義,，上述地區(qū)的人有多達(dá)三分之一的人缺乏ALDH2酶,。（生物谷：Bioon.com）
doi:10.1038/nature11368
PMC:
PMID:
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.
