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Functional characterization of an activating TEK mutation in acute myeloid leukemia: a cellular context-dependent activating mutation

Leukemia volume 23, pages 1345–1348 (2009)Cite this article

Therapies that are targeted to the molecular genetic defect of malignancies have proven more successful than conventional chemotherapeutic approaches.1, 2, 3, 4 A broad application of this strategy will require a detailed understanding of the genetic lesions involved in oncogenesis. Tyrosine kinases constitute a gene family of 91 members that play a critical role in numerous cellular processes, and aberrant regulation of tyrosine kinase activity has been observed in numerous types of malignancies.5 One malignancy in which tyrosine kinases are abnormally regulated is acute myeloid leukemia (AML). Several reports have shown that signal transducer and activator of transcription 5 (STAT5) is phosphorylated in blast cells from at least 70% of patients with AML.6, 7, 8 STAT5 phosphorylation is tightly controlled by tyrosine kinase signaling networks; hence this suggests the presence of aberrantly active, mutated tyrosine kinases in these patients.

To better understand the genetic lesions underlying this aberrant tyrosine kinase activity, we and others have recently performed large-scale sequencing screens of selected genes or entire cancer genomes.9, 10, 11, 12 This process revealed many non-synonymous sequence variants; however, functional characterization of most of these mutations failed to produce evidence supporting an oncogenic role for these mutations. We hypothesized that some of these ‘passenger’ mutations may have relevance to oncogenesis and that functional characterization by expression in standard murine cell lines failed due to the absence of a proper signaling machinery for the ectopically expressed human proteins. We here show that the expression of a mutated gene found in an individual AML patient, TEKG743A, does confer hypersensitivity to growth factor as well as increased basal phosphorylation of mitogenic signaling pathways in the human AML cell line, UT-7, but not in the murine pro-B cell line, Ba/F3. These data suggest that other ‘passenger’ mutations identified in large-scale sequencing screens may contribute to leukemogenesis and that the choice of cellular setting for functional follow-up studies is critical for the proper understanding of these mutant genes.

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Acknowledgements

This study was supported in part by The Leukemia and Lymphoma Society, the TJ Martell Foundation, and the Doris Duke Charitable Foundation. JWT is supported by a cancer biology training grant from the NIH, the William Lawrence Foundation, and by the Oregon Clinical and Translational Research Institute. BJD is an investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA

    J W Tyner, M L Rutenberg-Schoenberg, H Erickson, S G Willis, T O'Hare, M W Deininger, B J Druker & M M Loriaux

  2. Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR, USA

    T O'Hare & B J Druker

  3. Department of Pathology, Oregon Health & Science University, Portland, OR, USA

    M M Loriaux

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  1. J W Tyner
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Tyner, J., Rutenberg-Schoenberg, M., Erickson, H. et al. Functional characterization of an activating TEK mutation in acute myeloid leukemia: a cellular context-dependent activating mutation. Leukemia 23, 1345–1348 (2009). https://doi.org/10.1038/leu.2009.66

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