title: Gads (Grb2-related adaptor downstream of Shc) is required for BCR-ABL-mediated lymphoid leukemia.
abstract: Philadelphia chromosome-positive leukemias, including chronic myeloid leukemia and B-cell acute lymphoblastic leukemia (B-ALL), are driven by the oncogenic BCR-ABL fusion protein. Animal modeling experiments utilizing retroviral transduction and subsequent bone marrow transplantation have demonstrated that BCR-ABL generates both myeloid and lymphoid disease in mice receiving whole bone marrow transduced with BCR-ABL. Y177 of BCR-ABL is critical to the development of myeloid disease, and phosphorylation of Y177 has been shown to induce GRB2 binding to BCR-ABL, followed by activation of the Ras and phosphoinositide 3 kinase signaling pathways. We show that the GRB2-related adapter protein, GADS, also associates with BCR-ABL, specifically through Y177 and demonstrate that BCR-ABL-driven lymphoid disease requires Gads. BCR-ABL transduction of Gads(-/-) bone marrow results in short latency myeloid disease within 3-4 weeks of transplant, while wild-type mice succumb to both a longer latency lymphoid and myeloid diseases. We report that GADS mediates a unique BCR-ABL complex with SLP-76 in BCR-ABL-positive cell lines and B-ALL patient samples. These data suggest that GADS mediates lymphoid disease downstream of BCR-ABL through the recruitment of specific signaling intermediates.
authors: Campbell Family Cancer Research Institute, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors: L C
authors: LC
authors: Gillis
authors: D M
authors: DM
authors: Berry
authors: M D
authors: MD
authors: Minden
authors: C J
authors: CJ
authors: McGlade
authors: D L
authors: DL
authors: Barber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001773:Blood Cells / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation; D000071178:CD48 Antigen; D002460:Cell Line; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006411:Hematopoiesis, Extramedullary; D006801:Humans; D016130:Immunophenotyping; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism; D007945:Leukemia, Lymphoid / Q000235:genetics / Q000378:metabolism*; D054503:Lymphoid Progenitor Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000071178:CD48 Antigen; C409587:GRAP2 protein, human; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; C092947:SLP-76 signal Transducing adaptor proteins; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D016044:Fusion Proteins, bcr-abl
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