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)

被引:83
作者
Lowsky, R
DeCoteau, JF
Reitmair, AH
Ichinohasama, R
Dong, WF
Xu, Y
Mak, TW
Kadin, ME
Minden, MD
机构
[1] UNIV TORONTO,PRINCESS MARGARET HOSP,ONTARIO CANC INST,TORONTO,ON M5G 2M9,CANADA
[2] PRINCESS MARGARET HOSP,DEPT MED,TORONTO,ON M4X 1K9,CANADA
[3] PRINCESS MARGARET HOSP,DEPT PATHOL,TORONTO,ON M4X 1K9,CANADA
[4] BETH ISRAEL HOSP,DEPT PATHOL,BOSTON,MA 02215
[5] HARVARD UNIV,SCH MED,BOSTON,MA
[6] TOHOKU UNIV HOSP,DEPT PATHOL,SENDAI,MIYAGI,JAPAN
关键词
D O I
10.1182/blood.V89.7.2276
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (C) 1997 by The American Society of Hematology.
引用
收藏
页码:2276 / 2282
页数:7
相关论文
共 35 条
[1]   DOES ACTIVATION OF THE TAL1 GENE OCCUR IN A MAJORITY OF PATIENTS WITH T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA - A PEDIATRIC-ONCOLOGY-GROUP STUDY [J].
BASH, RO ;
HALL, S ;
TIMMONS, CF ;
CRIST, WM ;
AMYLON, M ;
SMITH, RG ;
BAER, R .
BLOOD, 1995, 86 (02) :666-676
[2]   THE 2 ISOFORMS OF MOUSE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE DIFFER IN BOTH THE ABILITY TO ADD N-REGIONS AND SUBCELLULAR-LOCALIZATION [J].
BENTOLILA, LA ;
DANDON, MF ;
NGUYEN, QT ;
MARTINEZ, O ;
ROUGEON, F ;
DOYEN, N .
EMBO JOURNAL, 1995, 14 (17) :4221-4229
[3]   GENETIC STEPS IN COLORECTAL-CANCER [J].
BODMER, W ;
BISHOP, T ;
KARRAN, P .
NATURE GENETICS, 1994, 6 (03) :217-219
[4]  
BOYER JC, 1995, CANCER RES, V55, P6063
[5]   A GERMLINE SUBSTITUTION IN THE HUMAN MSH2 GENE IS ASSOCIATED WITH HIGH-GRADE DYSPLASIA AND CANCER IN ULCERATIVE-COLITIS [J].
BRENTNALL, TA ;
RUBIN, CE ;
CRISPIN, DA ;
STEVENS, A ;
BATCHELOR, RH ;
HAGGITT, RC ;
BRONNER, MP ;
EVANS, JP ;
MCCAHILL, LE ;
BILIR, N ;
BOLAND, CR ;
RABINOVITCH, PS .
GASTROENTEROLOGY, 1995, 109 (01) :151-155
[6]  
BURKS RT, 1994, ONCOGENE, V9, P1163
[7]   THE T-CELL RECEPTOR BETA-CHAIN GENES ARE LOCATED ON CHROMOSOME-6 IN MICE AND CHROMOSOME-7 IN HUMANS [J].
CACCIA, N ;
KRONENBERG, M ;
SAXE, D ;
HAARS, R ;
BRUNS, GAP ;
GOVERMAN, J ;
MALISSEN, M ;
WILLARD, H ;
YOSHIKAI, Y ;
SIMON, M ;
HOOD, L ;
MAK, TW .
CELL, 1984, 37 (03) :1091-1099
[8]  
CLINE MJ, 1994, NEW ENGL J MED, V330, P328
[9]   INACTIVATION OF THE MOUSE MSH2 GENE RESULTS IN MISMATCH REPAIR DEFICIENCY, METHYLATION TOLERANCE, HYPERRECOMBINATION, AND PREDISPOSITION TO CANCER [J].
DEWIND, N ;
DEKKER, M ;
BERNS, A ;
RADMAN, M ;
RIELE, HT .
CELL, 1995, 82 (02) :321-330
[10]   MICE DEFICIENT FOR P53 ARE DEVELOPMENTALLY NORMAL BUT SUSCEPTIBLE TO SPONTANEOUS TUMORS [J].
DONEHOWER, LA ;
HARVEY, M ;
SLAGLE, BL ;
MCARTHUR, MJ ;
MONTGOMERY, CA ;
BUTEL, JS ;
BRADLEY, A .
NATURE, 1992, 356 (6366) :215-221