Therapy-induced malignant neoplasms in Nf1 mutant mice

Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, USA.
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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    ABSTRACT: Benzene is an established human leukemogen, with a ubiquitous environmental presence leading to significant population exposure. In a genome-wide functional screen in the yeast Saccharomyces cerevisiae, inactivation of IRA2, a yeast ortholog of the human tumor suppressor gene NF1 (Neurofibromin), enhanced sensitivity to hydroquinone, an important benzene metabolite. Increased Ras signaling is implicated as a causal factor in the increased pre-disposition to leukemia of individuals with mutations in NF1. Growth inhibition of yeast by hydroquinone was assessed in mutant strains exhibiting varying levels of Ras activity. Subsequently, effects of hydroquinone on both genotoxicity (measured by micronucleus formation) and proliferation of WT and Nf1 null murine hematopoietic precursors were assessed. Here we show that the Ras status of both yeast and mammalian cells modulates hydroquinone toxicity, indicating potential synergy between Ras signaling and benzene toxicity. Specifically, enhanced Ras signaling increases both hydroquinone-mediated growth inhibition in yeast and genotoxicity in mammalian hematopoetic precursors as measured by an in vitro erythroid micronucleus assay. Hydroquinone also increases proliferation of CFU-GM progenitor cells in mice with Nf1 null bone marrow relative to WT, the same cell type associated with benzene-associated leukemia. Together our findings show that hydroquinone toxicity is modulated by Ras signaling. Individuals with abnormal Ras signaling could be more vulnerable to developing myeloid diseases after exposure to benzene. We note that hydroquinone is used cosmetically as a skin-bleaching agent, including by individuals with cafe-au-lait spots (which may be present in individuals with neurofibromatosis who have a mutation in NF1), which could be unadvisable given our findings.
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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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