Abstract
Acquired resistance through genetic mutations is a major obstacle in targeted cancer therapy, but the underlying mechanisms are poorly understood. Here we studied mechanisms of acquired resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) by examining genome-wide gene expression changes in KCL-22 CML cells versus their resistant KCL-22M cells that acquire T315I BCR-ABL mutation following TKI exposure. Although T315I BCR-ABL is sufficient to confer resistance to TKIs in CML cells, surprisingly we found that multiple drug resistance pathways were activated in KCL-22M cells along with reduced expression of a set of myeloid differentiation genes. Forced myeloid differentiation by all-trans-retinoic acid (ATRA) effectively blocked acquisition of BCR-ABL mutations and resistance to the TKIs imatinib, nilotinib or dasatinib in our previously described in vitro models of acquired TKI resistance. ATRA induced robust expression of CD38, a cell surface marker and cellular NADase. High levels of CD38 reduced intracellular nicotinamide adenine dinucleotide (NAD+) levels and blocked acquired resistance by inhibiting the activity of the NAD+-dependent SIRT1 deacetylase that we have previously shown to promote resistance in CML cells by facilitating error-prone DNA damage repair. Consequently, ATRA treatment decreased DNA damage repair and suppressed acquisition of BCR-ABL mutations. This study sheds novel insight into mechanisms underlying acquired resistance in CML, and suggests potential benefit of combining ATRA with TKIs in treating CML, particularly in advanced phases.
Highlights
Chronic myeloid leukemia (CML) is a myeloproliferative disease resulting from the clonal hematopoietic stem cell disorder that is caused by the transformation of oncogenic breakpoint cluster region-Abelson (BCR-ABL) fusion gene [1]
CML progresses from chronic phase (CP) to accelerated phase (AP) into blast crisis (BC), which can be distinguished by the number and maturation of leukocytes
Acquired resistance through genetic mutations is a major mechanism for cancer drug resistance and accounts for the short life of targeted therapy in several types of human cancer
Summary
Chronic myeloid leukemia (CML) is a myeloproliferative disease resulting from the clonal hematopoietic stem cell disorder that is caused by the transformation of oncogenic breakpoint cluster region-Abelson (BCR-ABL) fusion gene [1]. Treatment with imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor, can effectively yield a durable complete cytogenetic response in CP patients and the drug is widely used as the first-line therapy for most CML patients [2]. The emergence of point mutations in the BCR-ABL kinase domain is a major cause of imatinib resistance in CML patients, especially in AP and BC [5,6]. These acquired mutations may alter kinase domain structure and impair drug binding affinity. More rational therapeutic strategies still need to be developed to overcome the problem of TKI resistance
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