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Molecular targets for therapy

DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells

Leukemia volume 31, pages 688–696 (2017)Cite this article

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Abstract

The FMS-like tyrosine kinase-3 (FLT3) gene is the most commonly mutated gene in acute myeloid leukemia (AML), and patients carrying internal tandem duplication (ITD) mutations have a poor prognosis. Long-term inhibition of FLT3 activity in these patients has been elusive. To provide a more complete understanding of FLT3 biology, a mass spectroscopy-based screen was performed to search for FLT3-interacting proteins. The screen identified dedicator of cytokinesis 2 (DOCK2), which is a guanine nucleotide exchange factor for Rho GTPases, and its expression is limited to hematolymphoid cells. We show that DOCK2 is expressed in leukemia cell lines and primary AML samples, and DOCK2 co-immunoprecipitates with wild-type FLT3 and FLT3/ITD. Knockdown (KD) of DOCK2 by shRNA selectively reduced cell proliferation and colony formation in leukemia cell lines with increased FLT3 activity, and greatly sensitized these cells to cytarabine treatment, alone and in combination with FLT3 tyrosine kinase inhibitors. DOCK2 KD in an FLT3/ITD-positive leukemia cell line also significantly prolonged survival in a mouse xenograft model. These findings suggest that DOCK2 is a potential therapeutic target for novel AML treatments, as this protein regulates the survival of leukemia cells with elevated FLT3 activity and sensitizes FLT3/ITD leukemic cells to conventional antileukemic agents.

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Acknowledgements

This work was supported by grants from the National Cancer Institute (R21CA175667 to AD and R01CA90668 to DS), and a Clinician Scientist Career Award from Johns Hopkins University (to AD). DS is also supported by the Kyle Haydock Professorship. We thank Dr Alan Tackett for expert assistance with mass spectrometry experiments and data analysis.

Author contributions

MW performed the experiments, analyzed the results and wrote the manuscript; MH performed the experiments, analyzed the results and revised the manuscript; LL performed the experiments and revised the manuscript; DS analyzed the results and revised the manuscript; AD designed the study, performed the experiments, analyzed the results and wrote the manuscript.

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Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA

    M Wu, M Hamaker & A S Duffield

  2. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD, USA

    L Li & D Small

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  1. M Wu
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Correspondence to A S Duffield.

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Wu, M., Hamaker, M., Li, L. et al. DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells. Leukemia 31, 688–696 (2017). https://doi.org/10.1038/leu.2016.284

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