Hnisz Denes, Weintraub Abraham S, Day Daniel S, Valton Anne-Laure, Bak Rasmus O, Li Charles H, Goldmann Johanna, Lajoie Bryan R, Fan Zi Peng, Sigova Alla A, Reddy Jessica, Borges-Rivera Diego, Lee Tong Ihn, Jaenisch Rudolf, Porteus Matthew H, Dekker Job, Young Richard A
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Science. 2016 Mar 25;351(6280):1454-1458. doi: 10.1126/science.aad9024. Epub 2016 Mar 3.
Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether 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 nonmalignant 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.
癌基因通过诸如基因融合、易位和局灶性扩增等众所周知的染色体改变而被激活。鉴于最近有证据表明关键基因的调控依赖于称为绝缘邻域的染色体结构，我们研究了原癌基因是否存在于这些结构中，以及癌基因激活是否可通过癌细胞中绝缘邻域边界的破坏而发生。我们绘制了T细胞急性淋巴细胞白血病（T-ALL）中的绝缘邻域图谱，发现肿瘤细胞基因组包含反复出现的微缺失，这些微缺失消除了包含重要T-ALL原癌基因的绝缘邻域的边界位点。在非恶性细胞中扰乱此类边界足以激活原癌基因。在许多类型的癌症中都发现了影响染色体邻域边界的突变。因此，癌基因激活可通过破坏恶性细胞中绝缘邻域的基因改变而发生。
