Inhibition of c-Myc overcomes cytotoxic drug resistance in acute myeloid leukemia cells by promoting differentiation.

Xiao-Na Pan,Le-Xun Wang,Zhi-Gang Fang,Zi-Jie Long,Ling-Ling Liu,Quentin Liu,Jia-Jie Chen,Dong-Jun Lin,Ruo-Zhi Xiao,Wei-Guo Zhu

doi:10.1371/journal.pone.0105381

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.

Highlights

Acute myeloid leukemia (AML) is a kind of aberrant clonal hematopoietic malignancy originating from genetic mutations, or epigenetic aberrations in normal hematopoietic progenitors
The result showed that NB4-R2 and K652/G were both resistant to anti-proliferative effect of cytarabine (Ara-C), DNR or Doxo, indicating that the two resistant leukemic cells had a broadspectrum of resistance to clinical cytotoxic drugs
Chemotherapy resistance was closely correlated to c-Myc amplification, we testify whether c-Myc overexpression was involved in the drug-resistant leukemic cells

Summary

Introduction

Acute myeloid leukemia (AML) is a kind of aberrant clonal hematopoietic malignancy originating from genetic mutations, or epigenetic aberrations in normal hematopoietic progenitors. Cytostatic drug resistance occurs through different mechanisms, including induction of drug detoxification [3], the over-expression of oncogene or inactivation of tumor suppressor gene [4,5], metabolic disturbance [6,7], as well as existence of leukemia stem cells [8]. Study reported that c-Myc over-expression was closely correlated to chemotherapy resistance in salivery carcinoma [17]. Inhibition of c-Myc overcame drug resistance in some cancers, such as Lewis lung carcinoma [18] and melanoma [19]. 10058F4, a targeted inhibitor of c-Myc, was reported to be effective in anti-tumor treatment, such as hepatocellular carcinoma [21] and leukemia [22]. The precise role of c-Myc in drug resistance of leukemic cells has not yet been elucidated

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Conclusion