Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells

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.