Abstract
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.
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