title: Inhibition of c-Myc overcomes cytotoxic drug resistance in acute myeloid leukemia cells by promoting differentiation.
abstract: Nowadays, drug resistance still represents a major obstacle to successful acute myeloid leukemia (AML) treatment and the underlying mechanism is not fully elucidated. Here, we found that high expression of c-Myc was one of the cytogenetic characteristics in the drug-resistant leukemic cells. c-Myc over-expression in leukemic cells induced resistance to chemotherapeutic drugs, enhanced colony formation capacity and inhibited cell differentiation induced by all-trans retinoic acid (ATRA). Meanwhile, inhibition of c-Myc by shRNA or specific c-Myc inhibitor 10058-F4 rescued the sensitivity to cytotoxic drugs, restrained the colony formation ability and promoted differentiation. RT-PCR and western blotting analysis showed that down-regulation of C/EBPβ contributed to the poor differentiation state of leukemic cells induced by c-Myc over-expression. Importantly, over-expression of C/EBPβ could reverse c-Myc induced drug resistance. In primary AML cells, the c-Myc expression was negatively correlated with C/EBPβ. 10058-F4, displayed anti-proliferative activity and increased cellular differentiation with up-regulation of C/EBPβ in primary AML cells. Thus, our study indicated that c-Myc could be a novel target to overcome drug resistance, providing a new approach in AML therapy.
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiao-Na
authors.initials: XN
authors.lastname: Pan
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Le-Xun
authors.initials: LX
authors.lastname: Wang
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ruo-Zhi
authors.initials: RZ
authors.lastname: Xiao
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Liu
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Fang
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D000970:Antineoplastic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; D014212:Tretinoin