多名研究人员Nature破解常见白血病基因组

　　

来自科技部的消息，西班牙奥维耶多大学（Universidad de Oviedo），英国桑格研究所（Wellcome Trust Sanger Institute）组建了多达60多名研究人员的研究组采用最新测序技术，破译慢性淋巴细胞白血病（Chronic lymphocytic leukaemia，CLL）的基因组，并找到了4个关键的基因。这对于这种疾病的诊断和治疗具有积极的意义。这一研究成果公布在Nature杂志上。

慢性淋巴细胞白血病简称慢淋，是一种起病缓慢的淋巴细胞系中某些免疫功能不全的淋巴细胞恶性增生性疾病。这种疾病在欧美白种人中常见的一种白血病。发病年龄大多在50岁以上、30岁以下者很少见。主要表现是全身淋巴结肿大，脾大，贫血及外周血中淋巴细胞异常增多。

据报道，2008年，西班牙确定以这种癌症类型作为首选，加入了国际肿瘤基因组协作组(International Cancer Genome Consortium, ICGC)研究计划，并组建了一支由60余名研究人员组成的团队，合作的医疗机构、高等院校和科研单位达12家之多，西班牙科学与创新部通过其所属的卡洛斯三世卫生研究院总计提供了1000万欧元资助。

这一研究团队近期完成了CLL基因组的测序分析，利用先进的测序技术对4名患者各自的癌细胞基因组与其正常细胞基因组进行了比对，按人类基因组30亿个核苷酸序列逐个检测，且每个序列至少读取30遍的工作量，反复验证，锁定了上千个突变的基因。并进一步结合对300多个病例的癌细胞基因组的分析，准确地找出了4个发生恶性突变的基因，破解了它们诱发慢性淋巴细胞白血病的机理。

近期混合系白血病治疗也获得了重要进展，来自英国伦敦国王学院的研究人员通过抑制两种蛋白质的功能来杀死引起这种白血病的干细胞，从而防止白血病发病或复发。

现有化疗等治疗手段往往只能杀死由病变干细胞形成的白血病细胞，对病变干细胞本身没有效果，这是混合系白血病难治的原因所在。而这项研究发现只有同时抑制这两种蛋白质，才能消灭混合系白血病的干细胞。这已在动物实验中获得证实，接下来将在此基础上开发适用于人类的临床疗法。

原文摘要：

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1, 2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3, 4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.