title: ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance.
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.
authors: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Zhiqiang
authors: Z
authors: Wang
authors: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Zheng
authors: Z
authors: Liu
authors: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Xiwei
authors: X
authors: Wu
authors: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Su
authors: S
authors: Chu
authors: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Jinhui
authors: J
authors: Wang
authors: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Hongfeng
authors: H
authors: Yuan
authors: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Mendel
authors: M
authors: Roth
authors: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Yate-Ching
authors: YC
authors: Yuan
authors: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: Ravi
authors: R
authors: Bhatia
authors: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors: WenYong
authors: W
authors: Chen
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D056564:Sirtuin 1 / Q000235:genetics; D013844:Thiazoles / Q000008:administration & dosage; D014212:Tretinoin / Q000008:administration & dosage*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D014212:Tretinoin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D051997:ADP-ribosyl Cyclase 1; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000069439:Dasatinib