Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice
- 17 July 2003
- journal article
- Published by Springer Nature in Oncogene
- Vol. 22 (29) , 4581-4585
- https://doi.org/10.1038/sj.onc.1206768
Abstract
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.Keywords
This publication has 23 references indexed in Scilit:
- Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell typeHuman Genetics, 2003
- Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences ofNf1 deficiency in T-cell development and functionBlood, 2002
- DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer SyndromesCancer Biology & Therapy, 2002
- DNA Mismatch Repair Deficiency Accelerates Endometrial Tumorigenesis in Pten Heterozygous MiceThe American Journal of Pathology, 2002
- Modeling myeloid leukemia tumor suppressor gene inactivation in the mouseSeminars in Cancer Biology, 2001
- Mlh1 deficiency enhances several phenotypes of ApcMin/+ miceOncogene, 2000
- Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DMA mismatch repairNature Genetics, 1998
- Homozygous Inactivation of theNF1Gene in Bone Marrow Cells from Children with Neurofibromatosis Type 1 and Malignant Myeloid DisordersNew England Journal of Medicine, 1997
- Tumour predisposition in mice heterozygous for a targeted mutation in Nf1Nature Genetics, 1994
- Loss of The Normal NF1 Allele from the Bone Marrow of Children with Type 1 Neurofibromatosis and Malignant Myeloid DisordersNew England Journal of Medicine, 1994