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

• Type of Material: Article
• Authors: Wei Liu, Case Western Reserve University; Wen-Mei Yu, Case Western Reserve University; Jing Zhang, Lanzhou University; Rebecca J. Chan, Indiana University; Mignon L. Loh, University of California; Zheng Zhang, Lanzhou University; Kevin Bunting, Emory University; Cheng-Kui Qu, Emory University
• Language: English
• Date: 2017-01-03
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Macmillan Publishers Limited, part of Springer Nature.
• Final Published Version (URL): http://dx.doi.org/10.1038/leu.2016.326
• Title of Journal or Parent Work: Leukemia
• ISSN: 0887-6924
• Grant/Funding Information: This work was supported by National Institutes of Health grants HL130995 and DK092722 and a Hyundai Hope on Wheels scholar grant (to C.K.Q.).
• Research Categories: Biology, Genetics; Health Sciences, Oncology

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 Ptpn11E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11E76K/+ mutation was markedly attenuated in Ptpn11E76K/+/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 Ptpn11E76K/+ 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.