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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA104282-01
Application #
6708744
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2004-05-01
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$279,518
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kane, Eleanor; Skibola, Christine F; Bracci, Paige M et al. (2015) Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium. Cancer Epidemiol Biomarkers Prev 24:1061-70
Chan, Gordon; Cheung, Laurene S; Yang, Wentian et al. (2011) Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells. Blood 117:4253-61
Niemeyer, Charlotte M; Kang, Michelle W; Shin, Danielle H et al. (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42:794-800
Loh, Mignon L; Sakai, Debbie S; Flotho, Christian et al. (2009) Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114:1859-63
Braun, Benjamin S; Shannon, Kevin (2008) Targeting Ras in myeloid leukemias. Clin Cancer Res 14:2249-52
Archambeault, Sophie; Flores, Nikki J; Yoshimi, Ayami et al. (2008) Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia. Blood 111:1124-7
Sovik, Oddmund; Schubbert, Suzanne; Houge, Gunnar et al. (2007) De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features. J Med Genet 44:e84
Diaz-Flores, Ernesto; Shannon, Kevin (2007) Targeting oncogenic Ras. Genes Dev 21:1989-92
Schubbert, Suzanne; Bollag, Gideon; Lyubynska, Natalya et al. (2007) Biochemical and functional characterization of germ line KRAS mutations. Mol Cell Biol 27:7765-70
Schubbert, Suzanne; Bollag, Gideon; Shannon, Kevin (2007) Deregulated Ras signaling in developmental disorders: new tricks for an old dog. Curr Opin Genet Dev 17:15-22

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