Role of PTPN11 Mutations in Myeloid Leukemogenesis

University Of California, San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): Myeloid malignancies are characterized by transformation in the stem cell compartment with clonal proliferation of progeny that demonstrate considerable variability with respect to the degree of differentiation, apoptosis, and blast proliferation. Genetic lesions found in myeloid malignancies including point mutations of the NRAS and KRAS proto-oncogenes, internal tandem duplications of the FLT3 receptor tyrosine kinase, and the BCR-ABL translocation contribute to leukemogenesis, at least in part, by deregulating signaling through p21ras (Ras) proteins. Juvenile myelomonocytic leukemia (JMML) is a relentless malignancy of young children characterized by over-production of myeloid lineage cells that infiltrate hematopoietic and non-hematopoietic tissues. The incidence of JMML is increased 200-500 fold in children with neurofibromatosis type 1 (NF1). This association is intriguing because the NF1 gene encodes neurofibromin, a GTPase activating protein that negatively regulates Ras output by accelerating GTP hydrolysis. Indeed, NF1 functions as a tumor suppressor in JMML, and mutually exclusive subsets of patients demonstrate oncogenic RAS mutations or NF1 inactivation. A few cases of JMML have been reported in children with Noonan Syndrome (NS). Recently, missense mutations in the PTPN11 gene were shown to cause -50% of NS. PTPN11 encodes SHP-2, a non-receptor tyrosine phosphatase that relays signals from many activated growth factor receptors to Ras and other effectors. We reasoned that somatic mutations in PTPN11 might exist in JMML and other myeloid malignancies, and present preliminary data that support this hypothesis. The overall goals of this project are to fully characterize the incidence and spectrum of these novel oncogenic mutations in myeloid malignancies, to investigate the biochemical and phenotypic consequences of expressing mutant SHP-2 molecules in cultured cells, and to develop mouse models.