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Br J Haematol. 2008 May;141(5):641-50. doi: 10.1111/j.1365-2141.2008.07090.x. Epub 2008 Mar 27.

THOC5 spliceosome protein: a target for leukaemogenic tyrosine kinases that affects inositol lipid turnover.

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1
Stem Cell and Leukaemia Proteomics Laboratory, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

Abstract

The fusion protein TEL/PDGFRB is associated with chronic myelomonocytic leukaemia and has intrinsic tyrosine kinase activity. The effects of TEL/PDGFRB were assessed using the multipotent haemopoietic cell line FDCP-Mix. In the absence of growth factors, TEL/PDGFRB expression increased survival that was associated with elevated levels of phosphatidylinositol 3,4,5 trisphosphate (PIP3). Whilst TEL/PDGFRB had subtle effects on the growth factor requirements it had a profound effect on differentiation. The cells became refractory to cytokine-stimulated development, showing limited maturation but failing to produce fully mature cells. We have previously identified the spliceosome protein THOC5 as a target in macrophage colony-stimulating factor signalling and a protein involved in the regulation of transcription factor expression. TEL/PDGFRB expression increased the expression and phosphorylation of THOC5. Elevated expression of THOC5 increased PIP3 levels and decreased apoptosis. Mass spectrometry was used to identify a site for TEL/PDGFRB-mediated phosphorylation on THOC5, which was shown to be a target for a number of other leukaemogenic tyrosine kinases. Thus, THOC5 is a novel target for modulation of signal transduction with a potential role in leukaemogenesis.

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