Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations

M. Golam Mohi, Ifor R. Williams, Charles R. Dearolf, Gordon Chan, Jeffery L. Kutok, Sarah Cohen, Kelly Morgan, Christina Boulton, Hirokazu Shigematsu, Heike Keilhack, Koichi Akashi, D. Gary Gilliland, Benjamin G. Neel

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)179-191
Number of pages13
JournalCancer Cell
Volume7
Issue number2
DOIs
Publication statusPublished - Feb 2005

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Juvenile Myelomonocytic Leukemia
Leukemia
Noonan Syndrome
Mutation
Germ-Line Mutation
Therapeutics
Phosphoric Monoester Hydrolases
Bone Marrow Cells
Drosophila
Tyrosine
Intercellular Signaling Peptides and Proteins
Carrier Proteins
Cytokines

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Mohi, M. G., Williams, I. R., Dearolf, C. R., Chan, G., Kutok, J. L., Cohen, S., ... Neel, B. G. (2005). Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell, 7(2), 179-191. https://doi.org/10.1016/j.ccr.2005.01.010

Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. / Mohi, M. Golam; Williams, Ifor R.; Dearolf, Charles R.; Chan, Gordon; Kutok, Jeffery L.; Cohen, Sarah; Morgan, Kelly; Boulton, Christina; Shigematsu, Hirokazu; Keilhack, Heike; Akashi, Koichi; Gilliland, D. Gary; Neel, Benjamin G.

In: Cancer Cell, Vol. 7, No. 2, 02.2005, p. 179-191.

Research output: Contribution to journalArticle

Mohi, MG, Williams, IR, Dearolf, CR, Chan, G, Kutok, JL, Cohen, S, Morgan, K, Boulton, C, Shigematsu, H, Keilhack, H, Akashi, K, Gilliland, DG & Neel, BG 2005, 'Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations', Cancer Cell, vol. 7, no. 2, pp. 179-191. https://doi.org/10.1016/j.ccr.2005.01.010
Mohi, M. Golam ; Williams, Ifor R. ; Dearolf, Charles R. ; Chan, Gordon ; Kutok, Jeffery L. ; Cohen, Sarah ; Morgan, Kelly ; Boulton, Christina ; Shigematsu, Hirokazu ; Keilhack, Heike ; Akashi, Koichi ; Gilliland, D. Gary ; Neel, Benjamin G. / Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. In: Cancer Cell. 2005 ; Vol. 7, No. 2. pp. 179-191.
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