High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression
High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression
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DOI：
10.1038/sj.leu.2404691
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发表时间：
2007-06-01
期刊：
影响因子：
11.4
通讯作者：
Hoogerbrugge, P. M.
中科院分区：
文献类型：
--
作者：
Kuiper, R. P.;Schoenmakers, E. F. P. M.;Hoogerbrugge, P. M.
大体细胞遗传学异常传统上被用作癌症（包括儿童急性淋巴细胞白血病（ALL））临床管理中的诊断、预后和治疗标志物。最近，越来越清楚的是，遗传性病变驱动肿瘤发生经常发生在亚显微水平，因此，逃脱标准的细胞遗传学观察。因此，我们以高分辨率分析了40个儿童ALL的基因组。我们检测到多个从头遗传病变，包括总的非整倍性和节段性增益和损失，其中一些是微妙的，影响单基因。这些病变中的许多涉及复发性（部分）重叠缺失和重复，包含各种已建立的白血病相关基因，如ETV 6，RUNX 1和MLL。重要的是，最常受影响的基因是那些控制G1/S细胞周期进程的基因（例如CDKN 2A，CDKN 1B和RB 1），其次是与B细胞发育相关的基因。后一组包括B系转录因子PAX 5、EBF、E2-2和IKZF 1（Ikaros）的微缺失，以及在B细胞发育中具有其他既定作用的基因，即RAG 1和RAG 2、FYN、PBEF 1或CBP/PAG。事实上，我们经常遇到影响细胞周期调控和B细胞分化相关基因的多个病变，这强烈表明这两个过程需要独立和同时靶向触发ALL的发展。
Gross cytogenetic anomalies are traditionally being used as diagnostic, prognostic and therapeutic markers in the clinical management of cancer, including childhood acute lymphoblastic leukemia (ALL). Recently, it has become increasingly clear that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we profiled the genomes of 40 childhood ALLs at high resolution. We detected multiple de novo genetic lesions, including gross aneuploidies and segmental gains and losses, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, containing various established leukemia-associated genes, such as ETV6, RUNX1 and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B and RB1), followed by genes associated with B-cell development. The latter group includes microdeletions of the B-lineage transcription factors PAX5, EBF, E2-2 and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, that is RAG1 and RAG2, FYN, PBEF1 or CBP/PAG. The fact that we frequently encountered multiple lesions affecting genes involved in cell cycle regulation and B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.