Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice.
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-/-;Nf1+/- mice were generated. All Mlh1-/-;Nf1+/- mice (n=21) were dead by 260 days compared to none of the Nf1+/- mice. In all, 50% of the Mlh1-/-;Nf1+/- 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 Nf1+/- 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 Nf1+/- mice, presumably by inactivating Nf1 gene expression.
Gutmann
D H
DH
Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA. gutmannd@neuro.wustl.edu
Winkeler
E
E
Kabbarah
O
O
Hedrick
N
N
Dudley
S
S
Goodfellow
P J
PJ
Liskay
R M
RM
D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D004260:DNA Repair / Q000235:genetics; D020868:Gene Silencing; D006579:Heterozygote; D006720:Homozygote; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins; D015996:Survival Rate; D013909:Thorax / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D025542:Neurofibromin 1; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1