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- Title
Upregulation of the TGFβ signalling pathway by Bcr-Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia
- Authors
Møller, Gigi M.O.; Frost, Victoria; Melo, Junia V.; Chantry, Andrew
- Abstract
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 TGFβ, 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 TGFβ/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 TGFβ compared to the parental TF-1 cell line. Additionally, growth of Bcr-Abl-expressing CD34+ cells from chronic phase CML patients is inhibited by TGFβ and, interestingly, treatment of a non-proliferating CD34+ CML cell sub-population with the TGFβ 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 TGFβ, and we hypothesise that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML.
- Subjects
CELL proliferation; DEATH (Biology); AMINO acids; TYROSINE
- Publication
FEBS Letters, 2007, Vol 581, Issue 7, p1329
- ISSN
0014-5793
- Publication type
Article
- DOI
10.1016/j.febslet.2007.02.048