Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations

W. Liu, W. M. Yu, J. Zhang, Rebecca Chan, M. L. Loh, Z. Zhang, K. D. Bunting, C. K. Qu

Research output: Contribution to journalArticle

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Abstract

Activating mutations, such as E76K and D61Y, in PTPN11 (SHP2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, are associated with 35% of patients with juvenile myelomonocytic leukemia (JMML), an aggressive childhood myeloproliferative neoplasm (MPN). Here we show that the interaction between leukemia-associated mutant Shp2 and Gab2, a scaffolding protein important for cytokine-induced PI3K/Akt signaling, was enhanced, and that the mTOR pathway was elevated in Ptpn11 E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11 E76K/+ mutation was markedly attenuated in Ptpn11 E76K/+/Gab2-/- double mutant mice-overproduction of myeloid cells was alleviated, splenomegaly was diminished and myeloid cell infiltration in nonhematopoietic organs was decreased in these double mutants. Excessive myeloid differentiation of stem cells was also normalized by depletion of Gab2. Acute leukemia progression of MPN was reduced in the double mutant mice and, as such, their survival was much prolonged. Furthermore, treatment of Ptpn11 E76K/+ mice with Rapamycin, a specific and potent mTOR inhibitor, mitigated MPN phenotypes. Collectively, this study reveals an important role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic signaling of the PTPN11 gain-of-function mutations and a therapeutic potential of Rapamycin for PTPN11 mutation-associated JMML.

Original languageEnglish (US)
Pages (from-to)1415-1422
Number of pages8
JournalLeukemia
Volume31
Issue number6
DOIs
StatePublished - Jun 1 2017

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Phosphatidylinositol 3-Kinases
Juvenile Myelomonocytic Leukemia
Mutation
Myeloid Cells
Sirolimus
Neoplasms
Leukemia
Myeloid Progenitor Cells
Protein Tyrosine Phosphatases
Splenomegaly
Cytokines
Phenotype
Survival
Therapeutics
Proteins

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. / Liu, W.; Yu, W. M.; Zhang, J.; Chan, Rebecca; Loh, M. L.; Zhang, Z.; Bunting, K. D.; Qu, C. K.

In: Leukemia, Vol. 31, No. 6, 01.06.2017, p. 1415-1422.

Research output: Contribution to journalArticle

Liu, W. ; Yu, W. M. ; Zhang, J. ; Chan, Rebecca ; Loh, M. L. ; Zhang, Z. ; Bunting, K. D. ; Qu, C. K. / Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. In: Leukemia. 2017 ; Vol. 31, No. 6. pp. 1415-1422.
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abstract = "Activating mutations, such as E76K and D61Y, in PTPN11 (SHP2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, are associated with 35{\%} of patients with juvenile myelomonocytic leukemia (JMML), an aggressive childhood myeloproliferative neoplasm (MPN). Here we show that the interaction between leukemia-associated mutant Shp2 and Gab2, a scaffolding protein important for cytokine-induced PI3K/Akt signaling, was enhanced, and that the mTOR pathway was elevated in Ptpn11 E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11 E76K/+ mutation was markedly attenuated in Ptpn11 E76K/+/Gab2-/- double mutant mice-overproduction of myeloid cells was alleviated, splenomegaly was diminished and myeloid cell infiltration in nonhematopoietic organs was decreased in these double mutants. Excessive myeloid differentiation of stem cells was also normalized by depletion of Gab2. Acute leukemia progression of MPN was reduced in the double mutant mice and, as such, their survival was much prolonged. Furthermore, treatment of Ptpn11 E76K/+ mice with Rapamycin, a specific and potent mTOR inhibitor, mitigated MPN phenotypes. Collectively, this study reveals an important role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic signaling of the PTPN11 gain-of-function mutations and a therapeutic potential of Rapamycin for PTPN11 mutation-associated JMML.",
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