DEFECTS OF THE MISMATCH REPAIR GENE MSH2 ARE IMPLICATED IN THE DEVELOPMENT OF MURINE AND HUMAN LYMPHOBLASTIC LYMPHOMAS AND ARE ASSOCIATED WITH THE ABERRANT EXPRESSION OF RHOMBOTIN-2 (LMO-2) AND TAL-1 (SCL)

Mutations in the DNA mismatch repair (MMR) gene hMSH2 underlie a novel pathway of tumorigenesis for some cancers of epithelial origin, Mice deficient in MSH2 are susceptible to lymphomas but defects in this gen e have not been identified in human lymphoid tumors. To determine if t he lymphomas these mice develop are related to a particular subtype of human lymphoma we evaluated 20 clinically ill homozygous MSH2(-/-) mi ce ranging in age from 2 to 13 months, The murine tumors comprised a s ingle histopathologic entity representing the malignant counterpart of precursor thymic T cells and closely resembled human precursor T-cell lymphoblastic lymphoma (LBL), Evaluation of the expression of three T -cell malignancy associated genes showed that Rhombotin-2 (RBTN-2 also known as Lmo-2), TAL-1 (also known as SCL), and HOX-11 were expressed in 100%, 40%, and 0% of the murine tumors, respectively, The MSH2(-/- ) murine model of precursor T-cell LBL was substantiated by the findin g of a nearly identical expression profile of RBTN-2, TAL-1, and HOX-1 1 in 10 well-characterized cases of human LBL. Direct evidence for MSH 2 abnormalities in human LBL was established by sequence analysis of e xon 13 of hMSH2, which revealed coding region mutations in 2 of 10 cas es, Our findings implicate defects in the MMR system with the aberrant expression of T-cell specific proto-oncogenes and define a new pathwa y of human lymphomagenesis. (C) 1997 by The American Society of Hemato logy.