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Gab2 is essential for Bcr-Abl-mediated leukemic transformation and hydronephrosis in a chronic myeloid leukemia mouse model

Leukemia volume 30, pages 1942–1945 (2016)Cite this article

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Chronic myeloid leukemia (CML) is driven by the hyperactive fusion kinase Bcr-Abl, resulting from a translocation between chromosomes 9 and 22. Bcr-Abl organizes a multimeric protein complex and activates various signaling pathways. In vitro experiments have shown that one critical component of the Bcr-Abl signaling complex is the docking protein Gab2, which is coupled to Bcr-Abl via the Grb2 adaptor.1, 2 These experiments demonstrated that Gab2 amplifies and channels Bcr-Abl signals to the Shp2/Ras/ERK, PI3K/AKT/mTOR and JAK/STAT5 pathways.2 Gab2 was first implicated in Bcr-Abl disease by retroviral transduction experiments using bone marrow (BM) from Gab2-deficient (Gab2−/−) mice. These experiments revealed an essential role of Gab2 for transformation by retrovirally expressed Bcr-Abl.3, 4 In addition, we demonstrated that Gab2 confers resistance to clinically approved Bcr-Abl inhibitors, including allosteric and third generation inhibitors such as ponatinib.5, 6, 7 We also showed that, in comparison with TKI-sensitive CML cells, the expression of this docking protein is increased in myeloid cells from patients with TKI-refractory disease5 or blast crisis,8 a stage known for its insensitivity to Bcr-Abl inhibitors.

In summary, we demonstrated for the first time that Gab2 deficiency has a profound effect on the course of disease in an in vivo CML model and protects against disease complications such as hydronephrosis. Our current and previous data5, 6, 7, 8 invites for further evaluation and consideration of Gab2 as a new biomarker for disease management or even as a new valuable therapeutic target in the treatment of CML. Given the fact that Gab2 has no enzymatic activity new approaches have to be developed such as targeting Gab2 protein–protein interactions.16

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Acknowledgements

This study was supported in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School) and the José Carreras Leukämie Stiftung e.V. (project 13/12). RZ and TB are supported by the Deutsche Forschungsgemeinschaft via the Heisenberg-Program and the Centre for Biological Signalling Studies BIOSS (EXC 294).

Author contributions

All authors designed, analyzed and discussed experiments. SH, MK and FMU performed all mouse experiments. KA and JH conducted the histology analysis. SH wrote the manuscript together with SK, RZ, KA and TB. All authors reviewed and commented on the manuscript and accepted its final version.

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Author notes

  1. K Aumann and T Brummer: Co-senior authors.

Authors and Affiliations

  1. Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany

    S Halbach, M Köhler & T Brummer

  2. Faculty of Biology, University of Freiburg, Freiburg, Germany

    S Halbach, M Köhler & F M Uhl

  3. Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany

    S Halbach & M Köhler

  4. Department of Medicine I, Hematology, Oncology and Stem-Cell Transplantation, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    F M Uhl & R Zeiser

  5. Center for Pathology, Institute of Surgical Pathology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    J Huber & K Aumann

  6. Comprehensive Cancer Center Freiburg CCCF, Medical Center—University of Freiburg, Freiburg, Germany

    J Huber, R Zeiser & T Brummer

  7. Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany

    R Zeiser & T Brummer

  8. Deutsches Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Freiburg, Germany

    R Zeiser & T Brummer

  9. Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    S Koschmieder

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  1. S Halbach
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Corresponding author

Correspondence to T Brummer.

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Halbach, S., Köhler, M., Uhl, F. et al. Gab2 is essential for Bcr-Abl-mediated leukemic transformation and hydronephrosis in a chronic myeloid leukemia mouse model. Leukemia 30, 1942–1945 (2016). https://doi.org/10.1038/leu.2016.92

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