Investigating a co-operative link between TGF-β and Lyn kinase in Chronic Myeloid Leukaemia

摘要: Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterised by uncontrolled proliferation of haematopoietic cells driven the fusion gene Bcr-Abl. The advent mechanism specific kinase inhibitor, Imatinib, targeting constitutively active Bcr-Abl has paved way for new treatment strategies. However, resistance emerges, particularly in those more advanced disease stages. One factor this presence quiescent subset CML that are insensitive to Imatinib. Imatinib linked with over-expression and activation Lyn, member Src family kinases (SFK). main aim project was investigate whether transforming growth factor-β (TGF) might influence drug-resistance through direct affects on Lyn levels its activation. This research builds previous findings Bcr-Abl-dependent up-regulation TGFβ signalling, implicating cytokine CML. Human MYL cell lines derived from patient were used show plays role imatinib-resistance effects protein turnover. Stimulation produced cyclic changes high molecular weight bands proteasomal inhibitors. These due TGF inducing ubiquitination, mediated via TGF-dependent expression c-cbl E3 ubiquitin ligase. Cell cycle analysis combination poly ADP ribose polymerase (PARP) cleavage assays causes quiescence, inhibition signalling pathway releases arrest enhances Imatinib-induced death. Collectively, data highlights potential dual-treatment approach using SB431542 enhance imatinib-mediated death in 5 CML. Furthermore, it speculated hyper-activation drives drug co-operative involving ubiquitination activation, which proto-oncogene.