TY - JOUR
T1 - Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations
AU - Mohi, M. Golam
AU - Williams, Ifor R.
AU - Dearolf, Charles R.
AU - Chan, Gordon
AU - Kutok, Jeffery L.
AU - Cohen, Sarah
AU - Morgan, Kelly
AU - Boulton, Christina
AU - Shigematsu, Hirokazu
AU - Keilhack, Heike
AU - Akashi, Koichi
AU - Gilliland, D. Gary
AU - Neel, Benjamin G.
N1 - Funding Information:
This work was supported by NIH grants R01 DK50693 (B.G.N.), P01 CA66996 (D.G.G.), and DK50654 (D.G.G.), and grants 6207-04 (B.G.N.) and 7059 (D.G.G.) from the Leukemia and Lymphoma Society. Histopathology services were supported by NIH grant P01 DK50654 to J.L.K. D.G.G. is an investigator of the HHMI. M.G.M was supported by a Hood Postdoctoral Fellowship from the Medical Foundation. C.R.D. was supported in part by NIH R24 RR15061.
PY - 2005/2
Y1 - 2005/2
N2 - The SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for growth factor and cytokine signaling. Germline Shp2 mutations cause Noonan Syndrome (NS), which is associated with increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations occur in sporadic JMML and other leukemias. We found that Shp2 mutants associated with sporadic leukemias transform murine bone marrow cells, whereas NS mutants are less potent in this assay. Transformation requires multiple domains within Shp2 and the Shp2 binding protein Gab2, and is associated with hyperactivation of the Erk, Akt, and Stat5 pathways. Mutant Shp2-transduced BM causes a fatal JMML-like disorder or, less commonly, lymphoproliferation. Shp2 mutants also cause myeloproliferation in Drosophila. Mek or Tor inhibitors potently inhibit transformation, suggesting new approaches to JMML therapy.
AB - The SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for growth factor and cytokine signaling. Germline Shp2 mutations cause Noonan Syndrome (NS), which is associated with increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations occur in sporadic JMML and other leukemias. We found that Shp2 mutants associated with sporadic leukemias transform murine bone marrow cells, whereas NS mutants are less potent in this assay. Transformation requires multiple domains within Shp2 and the Shp2 binding protein Gab2, and is associated with hyperactivation of the Erk, Akt, and Stat5 pathways. Mutant Shp2-transduced BM causes a fatal JMML-like disorder or, less commonly, lymphoproliferation. Shp2 mutants also cause myeloproliferation in Drosophila. Mek or Tor inhibitors potently inhibit transformation, suggesting new approaches to JMML therapy.
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U2 - 10.1016/j.ccr.2005.01.010
DO - 10.1016/j.ccr.2005.01.010
M3 - Article
C2 - 15710330
AN - SCOPUS:13844265841
SN - 1535-6108
VL - 7
SP - 179
EP - 191
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -
