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Transcriptional Control and Signal Transduction

A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5

Leukemia volume 27, pages 932–940 (2013)Cite this article

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Abstract

THOC5 is a member of the THO complex that is involved in processing and transport of mRNA. We have shown previously that hematopoietic stem cells have an absolute requirement for THOC5 for survival and that THOC5 is phosphorylated on tyrosine 225 as a consequence of leukemogenic protein tyrosine kinase (PTK) action. We have investigated pathways for THOC5 phosphorylation to develop an understanding of THO complex modulation by tyrosine kinase (TK) oncogenes in leukemias. We demonstrate that THOC5 phosphorylation is mediated by Src PTK and CD45 protein tyrosine phosphatase action and that this event is sensitive to oxidative status. We show that THOC5 phosphorylation is elevated in stem cells from patients with chronic myeloid leukemia (CML) and that this phosphorylation is sensitive to the frontline drugs used in CML treatment. Further we show that THOC5 Y225 phosphorylation governs mRNA binding. In addition, CXCL12 is shown to induce THOC5 Y225 phosphorylation, and site-directed mutagenesis demonstrates that this modulates motile response. In conclusion, we delineate a signaling pathway stimulated by leukemogenic PTKs, chemokines and oxidative stress that can affect THO complex mediation of gene expression describing mechanisms for post-transcriptional regulation of protein levels.

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Acknowledgements

This work was supported by Leukemia and Lymphoma Research UK Program 08004 and Grant 08071 and a CRUK Program C11074/A11008. This study was also supported by the Glasgow and Manchester Experimental Cancer Medicine Centers (ECMC), which is funded by Cancer Research UK and by the Chief Scientist’s Office Scotland (Glasgow). FG was additionally sponsored by the British Council with an Entente Cordiale Scholarship.

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Author notes

  1. F Griaud and A Pierce: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Stem Cell and Leukaemia Proteomics Laboratory, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Withington, Manchester, UK,

    F Griaud, A Pierce, M B Gonzalez Sanchez & A D Whetton

  2. Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, Glasgow, UK

    M Scott, S A Abraham & T L Holyoake

  3. Institut fuer Biochemie, OE4310, Medizinische Hochschule Hannover, Hannover, Germany

    D D H Tran & T Tamura

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  1. F Griaud
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Correspondence to A Pierce.

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Griaud, F., Pierce, A., Gonzalez Sanchez, M. et al. A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5. Leukemia 27, 932–940 (2013). https://doi.org/10.1038/leu.2012.283

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