Abstract
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.
Highlights
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) [1,2,3]
mycophenolic acid (MPA)-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis
We previously reported that treatment with mycophenolic acid (MPA) could induce CML cell death independently of the sensitivity to tyrosine kinase inhibitors (TKI) [10]
Summary
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) [1,2,3]. 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 tyrosinekinase 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. We and other have shown that amplification of Bcr-Abl, overexpression of stress proteins, or deregulation of Src kinases are among the mechanisms explaining resistance to imatinib and nilotinib [6,7,8,9]
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