Mutator phenotype in human hematopoietic neoplasms and its association with deletions disabling DNA repair genes and bcl-2 rearrangements

As mice carrying mutations of the DNA mismatch repair genes MSH2 and MSH6 o ften develop lymphoid neoplasms, we addressed the prevalence of the replica tion error (RER+) phenotype, a manifestation of an underlying defect of DNA mismatch repair genes, in human lymphoid tumors. We compared microsatellit e instability (MSI) at 10 loci in 37 lymphoid tumors, including 16 acute ly mphoid leukemias (ALL) and 21 non-Hodgkin's lymphomas (NHL), and in 29 acut e myeloid leukemias (AML). Significant differences in MSI prevalence betwee n AMLs and ALLs emerged, and MSI occurrence was more frequent in the NHLs v ersus AMLs. Indeed, only 3 of 29 (10%) AMLs exhibited MSI, thus confirming its paucity in myeloid tumors, while 10 of 37 (27%) lymphoid tumors, 6 ALLs and 4 NHLs. disclosed an RER+ phenotype. In 1 ALL patient, the same molecu lar alterations were observed in correspondence with a relapse, but were no t detected during remission over a 14-month follow-up; in another ALL patie nt, findings correlated with impending clinical relapse. These results sugg est that the study of MSI in lymphoid tumors might provide a useful molecul ar tool to monitor disease progression in a subset of ALLs. To correlate MS I with other known genetic abnormalities, we investigated the status of the proto-oncogene, bcl-2, in the lymphoma patients and found that 4 of 4 NHL patients with NISI carried bcl-2 rearrangements, thus linking genomic insta bility to enhanced cell survival in NHL; moreover, no p53 mutations were fo und in these patients. Finally, we addressed the putative cause of MSI in h ematopoietic tumors by searching for both mutations and deletions affecting DNA repair genes. A limited genetic analysis did not show any tumor-specif ic mutation in MLH1 exons 9 and 16 and in MSH2 exons 5 and 13. However, los s of heterozygosity (LOH) of markers closely linked to mismatch repair gene s MLH1. MSH2, and PMS2 was demonstrated in 4 of 6 ALLs and 1 of 3 AMLs with MSI. These observations indicate that chromosomal deletions might represen t a mechanism of inactivation of DNA repair genes in acute leukemia. (C) 19 99 by The American Society of Hematology.