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.
Subject(s)
Leukemia, Myeloid/genetics , Neoplasm Proteins/deficiency , Neurofibromatosis 1/genetics , Neurofibromin 1/genetics , Adaptor Proteins, Signal Transducing , Age Factors , Animals , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Base Pair Mismatch , Carrier Proteins , DNA Repair/genetics , Gene Silencing , Heterozygote , Homozygote , Leukemia, Myeloid/mortality , Leukemia, Myeloid/pathology , Mice , Mice, Knockout , MutL Protein Homolog 1 , Neoplasm Proteins/genetics , Neurofibromin 1/metabolism , Nuclear Proteins , Survival Rate , Thorax/pathologyABSTRACT
Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene cause the inherited disorder NF2 and are also common in malignant mesothelioma, which is not a characteristic feature of NF2. The authors report an asbestos-exposed person with NF2 and malignant mesothelioma. Immunohistochemical analysis of the mesothelioma confirmed loss of expression of the NF2 protein, and comparative genomic hybridization revealed losses of chromosomes 14, 15, and 22, and gain of 7. The authors propose that a person with a constitutional mutation of an NF2 allele is more susceptible to mesothelioma.
Subject(s)
Mesothelioma/complications , Mesothelioma/diagnosis , Neurofibromatosis 2/complications , Neurofibromatosis 2/diagnosis , Peritoneal Neoplasms/complications , Peritoneal Neoplasms/diagnosis , Adult , Fatal Outcome , Humans , Immunohistochemistry , Male , Mesothelioma/pathology , Neurofibromatosis 2/pathology , Neurofibromin 2/immunology , Peritoneal Neoplasms/pathologyABSTRACT
Individuals with the neurofibromatosis 1 (NF1) tumor predisposition syndrome develop low-grade pilocytic astrocytomas at an increased frequency. Previously, we demonstrated that astrocytes from mice heterozygous for a targeted mutation in the Nf1 gene (Nf1+/- astrocytes) exhibit a cell autonomous growth advantage associated with increased RAS pathway activation. In this report, we extend our initial characterization of the effect of reduced Nf1 gene expression on astrocyte function by demonstrating that Nf1+/- astrocytes exhibit decreased cell attachment, actin cytoskeletal abnormalities during the initial phases of cell spreading, and increased cell motility. Whereas these cytoskeletal abnormalities were also observed in Nf1-/- astrocytes, astrocytes expressing a constitutively active RAS molecule showed increased cell motility and abnormal actin cytoskeleton organization during cell spreading, but exhibited normal cell attachment. Based on ongoing gene expression profiling experiments on human astrocytoma tumors, we demonstrate increased expression of two proteins implicated in cell attachment, spreading and motility (GAP43 and T-cadherin) in Nf1+/- and Nf1-/- astrocytes. These results support the emerging notion that tumor suppressor gene heterozygosity results in abnormalities in cell function that may contribute to the pathogenesis of non-tumor phenotypes in NF1.