Upregulation of the TGFbeta signalling pathway by Bcr-Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia

Møller, Gigi M., Frost, Victoria, Melo, Junia V. and Chantry, Andrew (2007) Upregulation of the TGFbeta signalling pathway by Bcr-Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia. FEBS Letters, 581 (7). pp. 1329-1334. ISSN 0014-5793

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Abstract

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by uncontrolled growth of progenitor cells expressing the tyrosine kinase fusion gene product, Bcr-Abl. At present, little is known regarding how TGFß, and downstream Smad transcription factors, influence CML cell proliferation in the context of Bcr-Abl expression. Here we show that ectopic Bcr-Abl expression dramatically increases TGFß/Smad-dependent transcriptional activity in Cosl cells, and that this may be due to enhancement of Smad promoter activity. Bcr-Abl expressing TF-1 myeloid cells are more potently growth arrested by TGFß compared to the parental TF-1 cell line. Additionally, growth of Bcr-Abl-expressing CD34+ cells from chronic phase CML patients is inhibited by TGFß and, interestingly, treatment of a non-proliferating CD34+ CML cell sub-population with the TGFß kinase inhibitor SB431542 enhanced cell death mediated by the Bcr-Abl inhibitor imatinib. Our data suggest that the expression of Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGFß, and we hypothesise that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: EPrints Services
Date Deposited: 01 Oct 2010 13:38
Last Modified: 24 Jul 2019 15:22
URI: https://ueaeprints.uea.ac.uk/id/eprint/1408
DOI: 10.1016/j.febslet.2007.02.048

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