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- Title
Gads (Grb2-related adaptor downstream of Shc) is required for BCR-ABL-mediated lymphoid leukemia.
- Authors
Gillis, L C; Berry, D M; Minden, M D; McGlade, C J; Barber, D L
- 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.
- Subjects
ABL1 gene; LYMPHOCYTIC leukemia; B cell lymphoma; BONE marrow transplantation; MYELOID leukemia; CHROMOSOME abnormalities
- Publication
Leukemia (08876924), 2013, Vol 27, Issue 8, p1666
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2013.40