Myeloid malignancies are characterized by transformation in the stem cell compartment with clonal outgrowth of progeny that demonstrate considerable variability with respect to the degree of differentiation, apoptosis, and blast proliferation. Extensive experimental data implicate aberrant signal transduction as playing a fundamental role in leukemic growth. Mutant tyrosine kinases that contribute to myeloid leukemogenesis such as Flt3 and the BCR-ABL represent excellent targets for the development of molecular therapeutics. Although protein tyrosine phosphatases play an essential role in controlling kinase signaling networks, the role of these proteins in cancer pathogenesis has received limited attention. In studies supported by this project, we identified somatic mutations in the PTPN11 gene in ~35% of patients with juvenile myelomonocytic leukemia (JMML) and in ~5% of acute myeloid leukemias. PTPN11 encodes SHP-2, a non-receptor tyrosine phosphatase that relays signals from many activated growth factor receptors to Ras and other effectors. In other studies, we showed that leukemia-associated PTPN11 alleles encode gain-of-function SHP-2 proteins that induce aberrant hematopoietic progenitor colony growth. PTPN11 is thus the first human oncogene encoding a protein tyrosine phosphatase. Murine Ptpn11 mutant embryos succumb in utero with hematopoietic defects. We found that oncogenic KrasG12D does not rescue this phenotype, and unexpectedly discovered that SHP-2 phosphatase activity in not required for normal hematopoiesis. Germline PTPN11 mutations are also the predominant cause of Noonan Syndrome (NS), a common developmental disorder characterized by skeletal, cardiac, and hematologic abnormalities. Children with NS are at increased risk of developing JMML. In the course of investigating an unusual child with JMML, we unexpectedly identified germline KRAS mutations as a cause of NS. We have extensively characterized these mutant alleles, which encode amino acid substitutions not found in cancer. These observations have contributed substantially to the emerging paradigm that hyperactive Ras signaling through the Raf/MEK/ERK effector cascade plays a fundamental role in both development and cancer. We will use the additional two years of support to pursue the following research goals: (1) to perform mechanistic studies to elucidate how SHP-2 and Ras interact in hematopoiesis and myeloid growth control;and (2) to model germline KRAS mutations that cause human developmental disorders in the mouse and to use the novel strains to begin characterizing their phenotypic and biochemical consequences.
In research studies supported by this grant, we discovered mutations in a gene called PTPN11 in pediatric and adult leukemia, which makes a protein called SHP-2. These abnormal SHP-2 proteins cause leukemia and cause developmental disorders by turning on another important protein called Ras. The goals of our research are to understand how normal SHP-2 and Ras proteins regulate how cells grow and mature, to learn how the mutations that we have discovered contribute to cancer and other human diseases, and to use this knowledge to implement new treatments.
| 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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