Ataxia telangiectasia gene mutations in leukaemia and lymphoma
Ataxia telangiectasia gene mutations in leukaemia and lymphoma
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DOI：
10.1136/jcp.54.7.512
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发表时间：
2001-07-01
影响因子：
3.4
通讯作者：
Boultwood, J
中科院分区：
文献类型：
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作者：
Boultwood, J
共济失调毛细血管扩张症(AT)是一种罕见的多系统常染色体隐性遗传病，以神经元变性、基因组不稳定和癌症风险增加为特征。大约10%的AT纯合子患上癌症，主要是淋巴系统的癌症。AT患者的淋巴样恶性肿瘤既有B细胞来源，也有T细胞来源，包括霍奇金淋巴瘤、非霍奇金淋巴瘤和几种形式的白血病。20世纪80年代末，利用遗传连锁分析将AT基因座定位于染色体11q22-23区域，并在几年后通过定位克隆确定了致病基因。ATM基因编码一个很大的蛋白，属于一个具有高度保守的与磷脂酰肌醇3-激酶结构域相关的C-末端蛋白的蛋白家族。该激酶家族的成员在DNA损伤后的DNA修复和细胞周期检查点控制中发挥作用。最近的研究表明，ATM主要是在双链断裂时被激活的，可能被认为是基因组的看守人。ATM中的大多数突变会导致蛋白质的截断和不稳定，但某些错义和剪接错误已被证明会产生不那么严重的表型。杂合子患乳腺癌的风险略有增加。ATM缺陷小鼠表现出AT患者的许多症状，并且胸腺淋巴瘤的发生率很高。ATM基因突变与AT患者淋巴系统恶性肿瘤的高发以及ATN缺陷小鼠淋巴瘤的发生之间的关系，支持ATM基因失活在散发性淋巴系统恶性肿瘤发病机制中的重要作用。11q22-23(ATM基因的位置)杂合性缺失是淋巴系统恶性肿瘤中常见的事件。在罕见的散发性T细胞前淋巴细胞性白血病(T-PLL)、B细胞慢性淋巴细胞性白血病(B-CLL)以及最近的套细胞淋巴瘤(MCL)患者中，ATM基因频繁的失活突变已被报道。与AT的ATM突变模式不同，这些散发性淋巴系统恶性肿瘤中最常见的核苷酸变化是错义突变。在一些T-PLL、B-CLL和MCL患者中，ATM基因失活突变的存在，以及ATM基因正常拷贝的缺失，确立了ATM基因在淋巴系统恶性肿瘤发病机制中的体细胞失活，并强烈表明ATM作为肿瘤抑制因子发挥作用。已有报道在B-CLL患者的种系中存在错义突变，提示一些B-CLL患者可能是构成AT杂合子。B-CLL的假定遗传易感性，虽然耐人寻味，但值得进一步研究。
Ataxia telangiectasia (AT) is a rare multisystem, autosomal, recessive disease characterised by neuronal degeneration, genome instability, and an increased risk of cancer. Approximately 10% of AT homozygotes develop cancer, mostly of the lymphoid system. Lymphoid malignancies in patients with AT are of both B cell and T cell origin, and include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukaemia. The AT locus was mapped to the chromosomal region 11q22-23 using genetic linkage analysis in the late 1980s and the causative gene was identified by positional cloning several years later. The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. Most mutations in ATM result in truncation and destabilisation of the protein, but certain missense and splicing errors have been shown to produce a less severe phenotype. AT heterozygotes have a slightly increased risk of breast cancer. Atm deficient mice exhibit many of the symptoms found in patients with AT and have a high frequency of thymic lymphoma. The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atn deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy. Loss of heterozygosity at 11q22-23 (the location of the ATM gene) is a common event in lymphoid malignancy. Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL). In contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in these sporadic lymphoid malignancies were missense mutations. The presence of inactivating mutations, together with the deletion of the normal copy of the ATM gene in some patients with T-PLL, B-CLL, and MCL, establishes somatic inactivation of the ATM gene in the pathogenesis of lymphoid malignancies, and strongly suggests that ATM functions as a tumour suppressor. The presence of missense mutations in the germline of patients with B-CLL has been reported, suggesting that some patients with B-CLL may be constitutional AT heterozygotes. The putative hereditary predisposition of B-CLL, although intriguing, warrants further investigation.