title: Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia.
abstract: Understanding the complexity and dynamics of cancer cells in response to effective therapy requires hypothesis-driven, quantitative, and high-throughput measurement of genes and proteins at both spatial and temporal levels. This study was designed to gain insights into molecular networks underlying the clinical synergy between retinoic acid (RA) and arsenic trioxide (ATO) in acute promyelocytic leukemia (APL), which results in a high-quality disease-free survival in most patients after consolidation with conventional chemotherapy. We have applied an approach integrating cDNA microarray, 2D gel electrophoresis with MS, and methods of computational biology to study the effects on APL cell line NB4 treated with RA, ATO, and the combination of the two agents and collected in a time series. Numerous features were revealed that indicated the coordinated regulation of molecular networks from various aspects of granulocytic differentiation and apoptosis at the transcriptome and proteome levels. These features include an array of transcription factors and cofactors, activation of calcium signaling, stimulation of the IFN pathway, activation of the proteasome system, degradation of the PML-RARalpha oncoprotein, restoration of the nuclear body, cell-cycle arrest, and gain of apoptotic potential. Hence, this investigation has provided not only a detailed understanding of the combined therapeutic effects of RA/ATO in APL but also a road map to approach hematopoietic malignancies at the systems level.
authors.affiliation: State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Second Medical University, 197 Rui Jin Road II, Shanghai 200025, China.
authors.forename: Pei-Zheng
authors.initials: PZ
authors.lastname: Zheng
authors.forename: Kan-Kan
authors.initials: KK
authors.lastname: Wang
authors.forename: Qun-Ye
authors.initials: QY
authors.lastname: Zhang
authors.forename: Qiu-Hua
authors.initials: QH
authors.lastname: Huang
authors.forename: Yan-Zhi
authors.initials: YZ
authors.lastname: Du
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Zhang
authors.forename: Da-Kai
authors.initials: DK
authors.lastname: Xiao
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Shen
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.forename: Eric
authors.initials: E
authors.lastname: Eveno
authors.forename: Chun-Jun
authors.initials: CJ
authors.lastname: Zhao
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Chen
authors.forename: Hui-Yong
authors.initials: HY
authors.lastname: Fan
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Charles
authors.initials: C
authors.lastname: Auffray
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D004357:Drug Synergism; D015180:Electrophoresis, Gel, Two-Dimensional; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D010087:Oxides / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049490:Systems Biology / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide