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Biological properties of ligand-dependent activation of the MET receptor kinase in acute myeloid leukemia

Leukemia volume 29, pages 1218–1221 (2015)Cite this article

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Aberrant kinase signaling is a hallmark of myeloid malignancies that has become the focus of targeted therapies due to its integral role in leukemia cell proliferation and survival.1 In acute myeloid leukemia (AML) in particular, aberrant kinase signaling results from activating mutations of FLT3, KIT and NRAS or mutational inactivation of their negative regulators CBL, PTEN and PTPN11. However, recent genome-wide surveys have revealed that no more than 50% of patients possess activating genetic mutations in these kinase signaling pathways.2 This suggests that other mechanisms of kinase activation may exist.

Ligand-dependent activation of receptor tyrosine kinases (RTKs) has long been recognized as an alternative mechanism of aberrant kinase signaling. Indeed, it is now over three decades since Sporn and Todaro3 proposed their ‘autocrine hypothesis’ that postulated the essential functions of secreted factors in the promotion of autonomous cell growth required for malignant transformation. We now recognize many examples of carcinogenic autocrine signaling, involving ligands of the epidermal growth factor (EGF), insulin-like growth factor, platelet-derived growth factor, fibroblast growth factor, EPH, vascular endothelial growth factor, and Fms-like tyrosine kinase 3 (FLT3) and KIT receptors in AML specifically.4, 5, 6 Recently, autocrine activation of the MET receptor kinase was found in almost 40% of patients with AML, causing enhanced leukemia cell survival owing to aberrant expression of the MET ligand hepatocyte growth factor (HGF) that could be blocked by the competitive RTK inhibitor crizotinib.7, 8 However, translation of these findings into therapeutic clinical trials remains hindered by limited knowledge about the specific subtypes of AML in which MET activation occurs and by the development of resistance to MET kinase inhibitors due to the overexpression of HGF that adaptively reactivates MET signaling.8

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Acknowledgements

This research was supported by the National Institutes of Health grant K08CA160660, Gabrielle’s Angel Foundation and Alex’s Lemonade Stand Foundation (to AK) and the Leukemia and Lymphoma Society (to SMK).

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Author notes

  1. N Zhang

    Present address: 8Current address: Life Technologies Cooperation, 5791 Van Allen Way, Carlsbad, CA 92008, USA.,

Authors and Affiliations

  1. Department of Medicine, Mount Sinai St Luke’s-Roosevelt Hospital Center, New York, NY, USA

    S F McGee

  2. Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA

    S F McGee & A Kentsis

  3. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    S M Kornblau & Y Qiu

  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    A T Look

  5. Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    N Zhang & S-Y Yoo

  6. Departmentt of Biomedical Informatics, Ohio State University College of Medicine, Columbus, OH, USA

    K R Coombes

  7. Department of Pediatrics, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, Cornell University, New York, NY, USA

    A Kentsis

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Correspondence to S M Kornblau or A Kentsis.

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McGee, S., Kornblau, S., Qiu, Y. et al. Biological properties of ligand-dependent activation of the MET receptor kinase in acute myeloid leukemia. Leukemia 29, 1218–1221 (2015). https://doi.org/10.1038/leu.2014.348

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