Mismatch repair deficiency in hematological malignancies with microsatellite instability

Abstract

Mutations in human mismatch repair (MMR) genes are the genetic basis for certain types of solid tumors displaying microsatellite instability (MSI). MSI has also been observed in hematological malignancies, but whether these hematological malignancies are associated with MMR deficiency is still unclear. Using both biochemical and genetic approaches, this study analysed MMR proficiency in 11 cell lines derived from patients with hematological malignancies and demonstrated that six out of seven hematological cancer cell lines with MSI were defective in strand-specific MMR. In vitro complementation experiments, using characterized MMR mutant extracts or purified proteins, showed that these hematological cancer cells were defective in either hMutSα (a heterodimer of hMSH2 and hMSH6) or hMutLα (a heterodimer of hMLH1 and hPMS2). Furthermore, cell lines deficient in hMutSα showed large deletions or point mutations in hMSH2, while those deficient in hMutLα exhibited point mutations in hMLH1 or a lack of expression of hPMS2. From these results, we conclude that, as in solid tumors, hematological malignancies with MSI are also associated with MMR deficiency, and that the cause of MMR deficiency in these cell lines is due to a defective MutSα or MutLα. We also report here, for the first time, that an MSI-positive cell line derived from Burkitt's lymphoma is proficient in MMR.