Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells.
Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells.
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DNA错配修复酶（例如，MSH 2）保持基因组的完整性，它们的缺乏易导致几种人类癌症和耐药性。我们发现，来自新诊断的急性淋巴细胞白血病（ALL）患者的相当大比例（约11%）的白血病细胞具有低或不可检测的MSH 2蛋白水平（MSH 2-L），尽管有丰富的野生型MSH 2 mRNA。MSH 2-L白血病细胞含有1-4个调节MSH 2降解的基因（FRAP 1、HERC 1、PRKCZ、PIK 3C 2B）的部分或完全体细胞缺失;这些缺失也见于成人ALL（16%）和散发性结直肠癌（13.5%）。在人类白血病细胞中敲除这些基因通过增强MSH 2降解来重现MSH 2蛋白缺陷，导致DNA错配修复（MMR）显著减少并增加对硫嘌呤的抗性。这些发现揭示了一种以前未被认识到的机制，即调节MSH 2降解的基因的体细胞缺失导致白血病细胞中MSH 2蛋白水平检测不到，MMR缺陷和耐药性。
DNA mismatch repair enzymes (e.g., 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 patients (~11%) with newly diagnosed acute lymphoblastic leukemia (ALL) have low or undetectable MSH2 protein levels (MSH2-L), despite abundant wild-type MSH2 mRNA. MSH2-L leukemia cells contained partial or complete somatic deletions of 1–4 genes that regulate MSH2 degradation (FRAP1, HERC1, PRKCZ, PIK3C2B); these deletions were also found in adult ALL (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 significant reduction in DNA mismatch repair (MMR) 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, MMR deficiency and drug resistance.