title: Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1.
abstract: Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph(+)B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GRB2-associated binding protein 2 (GAB2) as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transducedGab2(-/-)bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors phosphatidylinositol 3-kinase (PI3K) or SRC homology 2-containing phosphotyrosine phosphatase 2 (SHP2). GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph(+)hematologic neoplasms.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Center, Toronto, ON, Canada;
authors.forename: Shengqing
authors.initials: S
authors.lastname: Gu
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA; Program in Molecular and Cellular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA;
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Chan
authors.affiliation: Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; and.
authors.forename: Golam
authors.initials: G
authors.lastname: Mohi
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA;
authors.forename: Joel
authors.initials: J
authors.lastname: Rosenbaum
authors.affiliation: Princess Margaret Cancer Center, Toronto, ON, Canada;
authors.forename: Azin
authors.initials: A
authors.lastname: Sayad
authors.affiliation: Princess Margaret Cancer Center, Toronto, ON, Canada;
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Princess Margaret Cancer Center, Toronto, ON, Canada;
authors.forename: Carl
authors.initials: C
authors.lastname: Virtanen
authors.affiliation: University of Massachusetts Medical School, Worcester, MA.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Center, Toronto, ON, Canada;
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA; Program in Molecular and Cellular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016044:Fusion Proteins, bcr-abl; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C490894:Gab2 protein, mouse; C516725:Ptpn11 protein, mouse