Oncotarget

Brief Reports:

A novel co-operative mechanism linking TGFβ and Lyn kinase activation to imatinib resistance in chronic myeloid leukaemia cells

Andrew Chantry _, Paul G Smith and Hideo Tanaka

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Oncotarget. 2012; 3:518-524. https://doi.org/10.18632/oncotarget.500

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Abstract

Paul G. Smith1, Hideo Tanaka2, and Andrew Chantry1

1 School of Biological Sciences, University of East Anglia, Norwich, UK

2 Department of Hematology, Hiroshima City Asa Hospital, Asakita-ku, Hiroshima, Japan.

3 EA2406, Université de Bordeaux, Bordeaux, France

Received: May 16, 2012; Accepted: May 22, 2012; Published: May 24, 2012

Keywords:Transforming growth factor-β, Smads, ubiquitin, c-cbl, Lyn, leukaemia

Correspondence:

Andrew Chantry, email:

Abstract

The advent of a mechanism specific inhibitor imatinib, targeting Bcr-Abl kinase, has paved the way for new treatment strategies in chronic myeloid leukaemia (CML). However, resistance to imatinib is common in patients and has recently been linked to both transforming growth factor-β (TGFβ) and elevated Lyn kinase activity, although molecular mechanisms remain largely unknown. Here, using leukaemic MYL cell lines derived from CML patients, we show that TGFβ plays a key role in imatinib-resistance via direct effects on Lyn ubiquitination and turnover that results in bursts of Lyn kinase activity, and identify c-cbl is a candidate E3 ubiquitin ligase. Furthermore, blockade of TGFβ signalling activity with the TGFβ receptor kinase inhibitor SB431542 significantly reduces Lyn turnover and activation, and subsequently enhances imatinib-mediated CML cell death in a proteasomal-dependent manner. Collectively, our data reveals novel co-operative mechanisms in CML involving TGFβ and Lyn kinase linked to proteasome function and ubiquitination, and thus supports therapeutic approaches that target TGFβ pathway activity as a strategy for overcoming imatinib-resistance in CML.


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