Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway

Molecular Cancer

Research

Dan-dan Xu¹  Li Zhang¹  Yu-ting Liu¹  Hai-zhao Yan¹  Yi Zhang²  Yi-fei Wang²  Hai-xuan Chen³  Wan-qun Chen³  Shao-xiang Wang⁴  Kai Zheng⁴  Shu-yan Zhou⁵  Xiao Wang⁶  Xiao-yan Wang⁶  Qiu-ying Liu⁶ 

[1] College of Life Science and Technology, Jinan University, 510632, Guangzhou, P.R, China;College of Life Science and Technology, Jinan University, 510632, Guangzhou, P.R, China;Institute of Biomedicine, Jinan University, 510632, Guangzhou, P.R China;College of Medicine, Jinan University, 510632, Guangzhou, P.R China;College of Medicine, Shenzhen University, 518020, Shenzhen, P.R China;Department of Pathological Physiology, Wan-nan Medical College, 241000, Wuhu, P.R China;Institute of Biomedicine, Jinan University, 510632, Guangzhou, P.R China;

关键词: Survivin;    Leukemia stem cell;    Sp1;    c-Myc;    ERK;    MSK pathway;   

DOI  :  10.1186/s12943-015-0326-0

 received in 2014-10-06, accepted in 2015-02-23,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundAcute myeloid leukemia (AML) is initiated and maintained by a subset of self-renewing leukemia stem cells (LSCs), which contribute to the progression, recurrence and therapeutic resistance of leukemia. However, the mechanisms underlying the maintenance of LSCs drug resistance have not been fully defined. In this study, we attempted to elucidate the mechanisms of LSCs drug resistance.MethodsWe performed reverse phase protein arrays to analyze the expression of anti-apoptotic proteins in the LSC-enriched leukemia cell line KG-1a. Immuno-blotting, cell viability and clinical AML samples were evaluated to verify the micro-assay results. The characteristics and transcriptional regulation of survivin were analyzed with the relative luciferase reporter assay, mutant constructs, chromatin immuno-precipitation (ChIP), quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR), and western blotting. The levels of Sp1, c-Myc, phospho-extracellular signal-regulated kinase (p-ERK), phospho-mitogen and stress-activated protein kinase (p-MSK) were investigated in paired CD34+ and CD34- AML patient samples.ResultsSurvivin was highly over-expressed in CD34 + CD38- KG-1a cells and paired CD34+ AML patients compared with their differentiated counterparts. Functionally, survivin contributes to the drug resistance of LSCs, and Sp1 and c-Myc concurrently regulate levels of survivin transcription. Clinically, Sp1 and c-Myc were significantly up-regulated and positively correlated with survivin in CD34+ AML patients. Moreover, Sp1 and c-Myc were further activated by the ERK/MSK mitogen-activated protein kinase (MAPK) signaling pathway, modulating survivin levels.ConclusionOur findings demonstrated that ERK/MSK/Sp1/c-Myc axis functioned as a critical regulator of survivin expression in LSCs, offering a potential new therapeutic strategy for LSCs therapy.

【 授权许可】

Unknown   
© Zhang et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.