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

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

SUBMITTER: Liu W 

PROVIDER: S-EPMC5462847 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature