title: 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 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.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH, USA.|Department of Pediatrics, Division of Hematology and Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA.
authors.forename: W-M
authors.initials: WM
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA.|The First Affiliated Hospital, Lanzhou University, Lanzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Chan
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of California, San Francisco, CA, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: The First Affiliated Hospital, Lanzhou University, Lanzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Bunting
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH, USA.|Department of Pediatrics, Division of Hematology and Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA.
authors.forename: C-K
authors.initials: CK
authors.lastname: Qu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C490894:Gab2 protein, mouse; C546843:mTOR protein, mouse; C516725:Ptpn11 protein, mouse