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

Loss of mismatch repair (MMR) genes is associated with poor cancer prognosis and has been reported to occur through genetic alterations that directly affect the expression of MMR genes such as MSH2 . This report identifies a subset of leukemia patients with reduced levels of MSH2 protein but without alterations in the MSH2 gene, and it identifies concurrent deletions in regulators of MSH2 stability as potential contributors to the MSH2 deficiency and associated drug resistance in this and other cancers. 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.