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Upregulation of the TGFβ signalling pathway by Bcr‐Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia
Author(s) -
Møller Gigi M.O.,
Frost Victoria,
Melo Junia V.,
Chantry Andrew
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.02.048
Subject(s) - cancer research , tyrosine kinase , ectopic expression , progenitor cell , biology , imatinib mesylate , myeloid , myeloid leukemia , smad , population , stem cell , cell growth , imatinib , breakpoint cluster region , microbiology and biotechnology , transforming growth factor , cell culture , signal transduction , medicine , receptor , biochemistry , environmental health , genetics
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.