A novel co-operative mechanism linking TGFβ and Lyn kinase activation to imatinib resistance in chronic myeloid leukaemia cells.
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.
School of Biological Sciences, University of East Anglia, Norwich, UK.
Paul G
PG
Smith
Hideo
H
Tanaka
Andrew
A
Chantry
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D004149:Dioxoles / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020239:Receptor Cross-Talk / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism*
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004149:Dioxoles; D010879:Piperazines; D011743:Pyrimidines; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000068877:Imatinib Mesylate; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C067419:CBL protein, human