We used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA). MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%). In contrast, cell cycle arrest and positive staining for senescence-associated β-galactosidase activity were detected for a large cell population (80%). MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis. In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease. 1. Introduction Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by a reciprocal translocation leading to the Philadelphia chromosome (Ph+) with a fusion gene BCR-ABL, the molecular hallmark of CML and Ph-positive acute lymphoblastic leukaemia (LAL) [1–3]. The resulting chimeric protein contains the kinase domain of the tyrosine kinase Abl N-terminal fused to a portion of Bcr including its dimerization domain [1]. The constitutive dimerization of Bcr-Abl results in the deregulated activation of the tyrosine-kinase driving uncontrolled proliferation and suppression of apoptosis in the affected hematopoietic cells. This pathophysiology explains the remarkable efficacy of Abl tyrosine kinase inhibitors (TKI) in controlling CML. Indeed, when exposed to TKI, Bcr-Abl expressing cells undergo apoptosis [4]. Although TKIs have represented a tremendous progress in the management of CML patients, resistances to TKI treatment have emerged. About a third of these resistances can be explained by the acquisition of additional mutations in the kinase domain of Abl. These mutations typically impede the inhibitor binding to its target, and second- generation inhibitors have been designed to overcome these resistances whenever possible. In the remaining resistant patients, the mechanisms are certainly more varied and often remain elusive. In an attempt to characterize and so to overcome resistance to TKI, we have generated K562-derived cell lines resistant to imatinib or nilotinib [5, 6]. We and other have shown that amplification of Bcr-Abl, overexpression of stress proteins, or deregulation of Src kinases are among the mechanisms
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