Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations.
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.
Mohi
M Golam
MG
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, NRB-1030, Boston, Massachusetts 02115, USA. gmohi@bidmc.harvard.edu
Williams
Ifor R
IR
Dearolf
Charles R
CR
Chan
Gordon
G
Kutok
Jeffery L
JL
Cohen
Sarah
S
Morgan
Kelly
K
Boulton
Christina
C
Shigematsu
Hirokazu
H
Keilhack
Heike
H
Akashi
Koichi
K
Gilliland
D Gary
DG
Neel
Benjamin G
BG
D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D004331:Drosophila melanogaster; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007377:Interleukin-3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D009374:Neoplasms, Experimental; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors
D018076:DNA, Complementary; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D049452:Green Fluorescent Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse