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Brief Definitive Report

^a Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202
^b Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202
^c Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202
^d Herman B.Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202
^e Howard Hughes Medical Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202
^f Department of Pediatrics, University of California at San Francisco School of Medicine, San Francisco, California 94143
Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut St., Rm. 421, Indianapolis, IN 46202.317-274-8679317-274-4719

dclapp{at}iupui.edu

Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's "two hit" model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1–/– murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W⁴¹ mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras–mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W⁴¹) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types.

Key Words: c-kit • mast cell • heterozygous • neurofibromatosis • tumor suppressor

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