Activation of proto-oncogenes by disruption of chromosome neighborhoods.
Activation of proto-oncogenes by disruption of chromosome neighborhoods.
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DOI：
10.1126/science.aad9024
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发表时间：
2016-03-25
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影响因子：
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通讯作者：
Young RA
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文献类型：
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作者：
Hnisz D;Weintraub AS;Day DS;Valton AL;Bak RO;Li CH;Goldmann J;Lajoie BR;Fan ZP;Sigova AA;Reddy J;Borges-Rivera D;Lee TI;Jaenisch R;Porteus MH;Dekker J;Young RA
癌基因通过众所周知的染色体改变被激活，包括基因融合、易位和局灶性扩增。最近的证据表明，关键基因的控制取决于被称为绝缘邻域的染色体结构，这促使我们研究原癌基因是否发生在这些结构中，以及癌基因激活是否可以通过破坏癌细胞中绝缘邻域边界而发生。我们绘制了T细胞急性淋巴细胞白血病（T-ALL）中的绝缘邻域，发现肿瘤细胞基因组包含复发性微缺失，消除了包含突出T-ALL原癌基因的绝缘邻域的边界位点。在非恶性细胞中，这种边界的扰动足以激活原癌基因。在许多类型的癌症中发现了影响染色体邻域边界的突变。因此，癌基因的激活可以通过破坏恶性细胞中隔离的邻近区域的遗传改变而发生。原癌基因可以通过破坏3D染色体结构的遗传改变来激活。
Oncogenes are activated through well-known chromosomal alterations, including gene fusion, translocation and focal amplification. Recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods led us to investigate whether proto-oncogenes occur within these structures and if oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T-cell acute lymphoblastic leukemia (T-ALL), and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in non-malignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells. One Sentence Summary Proto-oncogenes can be activated by genetic alterations that disrupt 3D chromosome structure.