Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice

被引：17
作者：
Gutmann, DH
Winkeler, E
Kabbarah, O
Hedrick, N
Dudley, S
Goodfellow, PJ
Liskay, RM
机构：
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA
[3] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
来源：
ONCOGENE | 2003年 / 22卷 / 29期
关键词：
tumor suppressor gene; mismatch repair; leukemia; neurofibromin;
D O I：
10.1038/sj.onc.1206768
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Defects in DNA mismatch repair (MMR) have been implicated in the genesis of a diverse set of human cancers. Recent studies have suggested that one of the targets of MMR is the neurofibromatosis 1 (NF1) gene. To evaluate the contribution of Mlh1 MMR deficiency to Nf1 tumorigenesis, Mlh1 - / -; Nfl + / - mice were generated. All Mlh1 - / -; Nfl +/- mice (n = 21) were dead by 260 days compared to none of the Nf1 + / - mice. In all, 50% of the Mlh1 - / -; Nfl +/- mice were dead at 150 days compared to 252 days for Mlh1 - / - mice. Nine of the Mlh1 - / -; Nf1 + / - mice were found to harbor intrathoracic NOS2-immunoreactive myeloid leukemias similar to the hematopoietic malignancies observed in older Nfl + / - mice. As expected, significant microsatellite instability was observed in six of six tumors and neurofibromin expression was lost in all tumors analysed. These results suggest that MMR deficiency can accelerate myeloid leukemogenesis in Nfl + / - mice, presumably by inactivating Nf1 gene expression.
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收藏
页码：4581 / 4585
页数：5
相关论文
共 33 条
[1]   Nf1 and Gmcsf interact in myeloid leukemogenesis [J].
Birnbaum, RA ;
O'Marcaigh, A ;
Wardak, Z ;
Zhang, YY ;
Dranoff, G ;
Jacks, T ;
Clapp, DW ;
Shannon, KM .
MOLECULAR CELL, 2000, 5 (01) :189-195
[2]  
Boland CR, 1998, CANCER RES, V58, P5248
[3]  
Buermeyer AB, 1999, CANCER RES, V59, P538
[4]   Genotypic and phenotypic progression in endometrial tumorigenesis:: Determining when defects in DNA mismatch repair and KRAS2 occur [J].
Cohn, DE ;
Mutch, DG ;
Herzog, TJ ;
Rader, JS ;
Dintzis, SM ;
Gersell, DJ ;
Todd, CR ;
Goodfellow, PJ .
GENES CHROMOSOMES & CANCER, 2001, 32 (04) :295-301
[5]  
Cooper LJN, 2000, BLOOD, V96, P2310
[6]  
Edelmann W, 1999, CANCER RES, V59, P1301
[7]   The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2 [J].
Gutmann, DH ;
Aylsworth, A ;
Carey, JC ;
Korf, B ;
Marks, J ;
Pyeritz, RE ;
Rubenstein, A ;
Viskochil, D .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1997, 278 (01) :51-57
[8]   Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas [J].
Gutmann, DH ;
Donahoe, J ;
Brown, T ;
James, CD ;
Perry, A .
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2000, 26 (04) :361-367
[9]   DNA repair and tumorigenesis - Lessons from hereditary cancer syndromes [J].
Heinen, CD ;
Schmutte, H ;
Fishel, R .
CANCER BIOLOGY & THERAPY, 2002, 1 (05) :477-485
[10]   Lymphoproliferative defects in mice lacking the expression of neurofibromin:: functional and biochemical consequences of Nf1 deficiency in T-cell development and function [J].
Ingram, DA ;
Zhang, L ;
McCarthy, J ;
Wenning, MJ ;
Fisher, L ;
Yang, FC ;
Clapp, DW ;
Kapur, R .
BLOOD, 2002, 100 (10) :3656-3662
1234