Learning from a paradox: recent insights into Fanconi anaemia through studying mouse models.
Learning from a paradox: recent insights into Fanconi anaemia through studying mouse models.
复制标题
DOI：
10.1242/dmm.009795
复制
发表时间：
2013-01
影响因子：
4.3
通讯作者：
te Riele H
中科院分区：
文献类型：
--
作者：
Bakker ST;de Winter JP;te Riele H
范可尼贫血（FA）是一种罕见的常染色体隐性遗传或X连锁遗传疾病，其特征是骨髓衰竭（BMF）、血液学恶性肿瘤和实体瘤的发生率增加。FA患者的细胞对DNA链间交联（ICL）诱导剂表现出明显的敏感性，表现为G2-M期阻滞、染色体畸变和细胞存活率降低。迄今为止，已经确定了至少15种不同基因的突变导致FA;所有这些基因的产物被认为在FA途径中一起起作用，这对ICL修复至关重要。在发现FA基因后，突变小鼠被用来研究疾病和受影响的途径。这些突变小鼠均表现出特征性的细胞ICL诱导剂敏感性，但仅部分重现了FA个体中观察到的发育异常、贫血和癌症易感性。因此，在小鼠中模拟FA的有用性受到质疑。在这篇评论中，我们认为这种怀疑是没有道理的。我们概述了造血缺陷和癌症易感性是小鼠FA基因缺陷的表现，尽管仅在某些遗传背景和某些条件下。最重要的是，最近的工作表明，FA小鼠的发育缺陷也伴随着乙醛代谢的失活而出现，这为内源性病变的性质提供了强有力的线索，这些病变必须通过功能性FA途径进行修复。这项工作为FA研究中的一个悖论提供了一个很好的例子：小鼠和人类之间的差异，而不是相似性，可以提供对人类疾病的洞察。我们希望对FA小鼠模型的进一步研究将有助于揭示FA的机制背景，最终为该疾病提供更好的治疗方案。
Fanconi anaemia (FA) is a rare autosomal recessive or X-linked inherited disease characterised by an increased incidence of bone marrow failure (BMF), haematological malignancies and solid tumours. Cells from individuals with FA show a pronounced sensitivity to DNA interstrand crosslink (ICL)-inducing agents, which manifests as G2-M arrest, chromosomal aberrations and reduced cellular survival. To date, mutations in at least 15 different genes have been identified that cause FA; the products of all of these genes are thought to function together in the FA pathway, which is essential for ICL repair. Rapidly following the discovery of FA genes, mutant mice were generated to study the disease and the affected pathway. These mutant mice all show the characteristic cellular ICL-inducing agent sensitivity, but only partially recapitulate the developmental abnormalities, anaemia and cancer predisposition seen in individuals with FA. Therefore, the usefulness of modelling FA in mice has been questioned. In this Review, we argue that such scepticism is unjustified. We outline that haematopoietic defects and cancer predisposition are manifestations of FA gene defects in mice, albeit only in certain genetic backgrounds and under certain conditions. Most importantly, recent work has shown that developmental defects in FA mice also arise with concomitant inactivation of acetaldehyde metabolism, giving a strong clue about the nature of the endogenous lesion that must be repaired by the functional FA pathway. This body of work provides an excellent example of a paradox in FA research: that the dissimilarity, rather than the similarity, between mice and humans can provide insight into human disease. We expect that further study of mouse models of FA will help to uncover the mechanistic background of FA, ultimately leading to better treatment options for the disease.
登录
查看更多内容
DOI：
10.1056/nejmra0809889
发表时间：
2010-05-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
20.3
作者：
Freie, B;Li, XX;Clapp, DW
通讯作者：
Clapp, DW
DOI：
10.1038/nrc3088
发表时间：
2011-06-24
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1056/nejmra0903373
发表时间：
2009-12-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Calado RT;Young NS
通讯作者：
Young NS
影响因子：
7.3
作者：
Bakker, Sietske T.;van de Vrugt, Henri J.;Riele, Hein Te
通讯作者：
Riele, Hein Te