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Animal Models

Gads (Grb2-related adaptor downstream of Shc) is required for BCR-ABL-mediated lymphoid leukemia

Leukemia volume 27, pages 1666–1676 (2013)Cite this article

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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.

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Acknowledgements

We thank Renu Sarao and Amanda Luck for animal colony management and Mojib Javadi for final figure preparation. This research was supported by operating funds from Leukemia and Lymphoma Society of Canada (to CJM and DLB) and Canadian Institutes of Health Research—MOP#12859 (CJM) and MOP#42428 (DLB).

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Authors and Affiliations

  1. Campbell Family Cancer Research Institute, Ontario Cancer Institute, Toronto, Ontario, Canada

    L C Gillis, M D Minden & D L Barber

  2. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    L C Gillis, M D Minden, C J McGlade & D L Barber

  3. Hospital for Sick Children, Toronto, Ontario, Canada

    D M Berry & C J McGlade

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  1. L C Gillis
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Correspondence to C J McGlade or D L Barber.

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Gillis, L., Berry, D., Minden, M. et al. Gads (Grb2-related adaptor downstream of Shc) is required for BCR-ABL-mediated lymphoid leukemia. Leukemia 27, 1666–1676 (2013). https://doi.org/10.1038/leu.2013.40

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