The Lyn-SIRT1 signaling pathway is involved in imatinib resistance in chronic myeloid leukaemia.

BACKGROUND Imatinib resistance is commonly associated with the activation of BCR-ABL signaling in chronic myeloid leukaemia (CML). The activation of Lyn can result in imatinib resistance by regulating the formation of BCR-ABL protein complexes. SIRT1 is a novel survival pathway activated by BCR-ABL expression in haematopoietic progenitor cells. This study aimed to investigate whether the signaling pathway of Lyn/BCR-ABL/SIRT1 could mediate imatinib resistance in CML. METHODS The MTT assay was used to detect cell viability. Apoptosis was measured by a flow cytometry assay. Protein expression was detected by Western blotting. Knockdown CML cells were constructed by shRNA interference. The CML mouse model was used to investigate the role of SIRT1 in CML in vivo. RESULTS Lyn was overexpressed in K562R cells. BCR-ABL phosphorylation and activation were promoted by Lyn. Imatinib suppressed BCR-ABL phosphorylation in both K562 and K562R cells. BCR-ABL positively regulated SIRT1 and Foxo1 but negatively regulated acetylated Foxo1 (Ac-Foxo1) and p53 expression. Pharmacological inhibition of SIRT1 or knockdown of SIRT1 increased apoptosis and reduced growth in vitro and in vivo. Foxo1 was downregulated by SIRT1 inhibition or knockdown, while Ac-Foxo1 and p53 were upregulated. In vivo experiments showed that imatinib and/or SIRT1 inhibition both prolonged the survival of the CML mouse model and that the effects of imatinib were enhanced in combination with SIRT1 inhibition. CONCLUSION We proposed a novel molecular mechanism of imatinib resistance in CML in which the high expression of Lyn in imatinib-resistant cells inhibited Ac-Foxo1 and p53 expression through the BCR-ABL/SIRT1/Foxo1 signaling pathway, thus reducing apoptosis and mediating imatinib resistance.