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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)
R Lowsky, JF DeCoteau, AH Reitmair, R Ichinohasama, WF Dong, Y Xu, TW Mak, ME Kadin and MD Minden
Department of Medicine, University of Toronto, Ontario, Canada.
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 gene
have not been identified in human lymphoid tumors. To determine if the
lymphomas these mice develop are related to a particular subtype of human
lymphoma we evaluated 20 clinically ill homozygous MSH2-/- mice ranging in
age from 2 to 13 months. The murine tumors comprised a single
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 finding of a nearly identical
expression profile of RBTN-2, TAL-1, and HOX-11 in 10 well-characterized
cases of human LBL. Direct evidence for MSH2 abnormalities in human LBL was
established by sequence analysis of exon 13 of hMSH2, which revealed coding
region mutations in 2 of 10 cases. Our findings implicate defects in the
MMR system with the aberrant expression of T-cell specific proto-oncogenes
and define a new pathway of human lymphomagenesis.
Volume 89,
Issue 7,
pp. 2276-2282,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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