Therapy-induced malignant neoplasms in Nf1 mutant mice

University of California, Davis, Davis, California, United States
Cancer Cell (Impact Factor: 23.52). 11/2005; 8(4):337-48. DOI: 10.1016/j.ccr.2005.08.011
Source: PubMed


Therapy-induced cancers are a severe complication of genotoxic therapies. We used heterozygous Nf1 mutant mice as a sensitized genetic background to investigate tumor induction by radiation (RAD) and cyclophosphamide (CY). Mutagen-exposed Nf1(+/-) mice developed secondary cancers that are common in humans, including myeloid malignancies, sarcomas, and breast cancers. RAD cooperated strongly with heterozygous Nf1 inactivation in tumorigenesis. Most of the solid tumors showed loss of the wild-type Nf1 allele but retained two Trp53 alleles. Comparative genomic hybridization demonstrated distinct patterns of copy number aberrations in sarcomas and breast cancers from Nf1 mutant mice, and tumor cell lines showed deregulated Ras signaling. Nf1(+/-) mice provide a tractable model for investigating the pathogenesis of common mutagen-induced cancers and for testing preventive strategies.

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    • "Homozygous inactivation of a conditional mutant allele of murine Nf1 in the hematopoietic compartment results in a progressive MPD that models JMML [18]. Heterozygous Nf1 mutant mice are also susceptible to myelodysplastic syndrome (MDS) and other genotoxin-induced cancers, and appear to be particularly sensitive to the mutagenic effects of radiation [19,20]. As with IRA2 in yeast, NF1 mutations lead to hyperactive Ras signaling [21,22], and are consistent with the high prevalence of somatic NRAS and KRAS mutations in these cancers. "
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    • "As expected from previous reports (Jacks 1994, Brannan 1994, Maghoub 1999, Chao 2005), the survival of unirradiated Nf1 +/− mice was reduced compared to WT littermates (p=0.02, logrank test) with deaths occurring after one year of age (Figure 1A). "
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    • "The relationship between heritable mutations and these treatments is not yet clear, although in laboratory models alkylating agents increase the incidence of myeloproliferative disorder with reduced latency in Nf1 mutant mice [Mahgoub et al., 1999]. Moreover, the combination of radiation and alkylating agents induces a spectrum of soft tissue sarcomas and breast carcinomas with subsequent inactivation of the normal Nf1 allele and, in some cases, loss of heterozygosity at the Trp53 locus [Chao et al., 2005]. This suggests that there may be some combined effect of chemotherapy and radiation on the development of secondary malignancies in some patients with underlying genetic cancer predisposition. "
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