Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Nat Med. 2011 Sep 25;17(10):1298-303. doi: 10.1038/nm.2430.
DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency predisposes to several human cancers and to drug resistance. We found that leukemia cells from a substantial proportion of children (∼11%) with newly diagnosed acute lymphoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRNA. Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRKCZ and PIK3C2B); we also found these deletions in individuals with adult acute lymphoblastic leukemia (16%) and sporadic colorectal cancer (13.5%). Knockdown of these genes in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DNA mismatch repair and increased resistance to thiopurines. These findings reveal a previously unrecognized mechanism whereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair deficiency and drug resistance.
DNA 错配修复酶（例如，MSH2）维持基因组完整性，其缺陷易导致多种人类癌症和耐药性。我们发现，相当一部分新诊断为急性淋巴细胞白血病的儿童（约 11%）的白血病细胞中，MSH2 蛋白水平低或无法检测到，尽管存在大量野生型 MSH2 mRNA。MSH2 水平低的白血病细胞含有部分或完全缺失一个至四个调节 MSH2 降解的基因（FRAP1（也称为 MTOR）、HERC1、PRKCZ 和 PIK3C2B）；我们还在成年急性淋巴细胞白血病患者（16%）和散发性结直肠癌患者（13.5%）中发现了这些缺失。在人类白血病细胞中敲低这些基因，通过增强 MSH2 降解，重现了 MSH2 蛋白缺乏，导致 DNA 错配修复减少和对硫嘌呤类药物的耐药性增加。这些发现揭示了一种先前未被认识的机制，即调节 MSH2 降解的基因的体细胞缺失导致白血病细胞中无法检测到 MSH2 蛋白、DNA 错配修复缺陷和耐药性。
