title: NPMc(+) AML cell line shows differential protein expression and lower sensitivity to DNA-damaging and p53-inducing anticancer compounds.
abstract: Nucleophosmin (NPM), an important regulator in p53 signaling pathway, is one of the most frequently mutated genes in acute myeloid leukemia (AML). In our previous study, we found that hexamethylene bisacetamide inducible protein 1 (HEXIM1) interacted with both wild-type NPM and cytoplasmic-misallocated NPMc(+) mutant, leading to an increase in RNA polymerase II transcription. Here, we examine the protein expression in wild-type NPM (AML2) and NPMc(+) mutant (AML3) AML cell lines. Significant lower levels of NPM, HEXIM1 and p53 proteins are detected in AML3 cells, and such differential protein expression is not regulated at transcriptional or post-translational stages. Effects of several anticancer compounds on cell viability of AML2 and AML3 cells are investigated. Compared to AML3 cells, AML2 cells are more sensitive to the treatment of the DNA-damaging compounds (doxorubicin and etoposide) and a specific p53-inducing compound (nutlin-3). However, no significant difference in cytotoxicity was observed when AML2 and AML3 cells were treated with cyclin-dependent kinase inhibitors, flavopiridol and CYC202. Our results provide a novel insight into the functional impact of the NPMc(+) mutation on protein expression and the potential approaches for selective therapy of AML.
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore.
authors.forename: Qiao Jing
authors.initials: QJ
authors.lastname: Lew
authors.forename: Chuan Hao
authors.initials: CH
authors.lastname: Tan
authors.forename: Meera
authors.initials: M
authors.lastname: Gurumurthy
authors.forename: Kai Ling
authors.initials: KL
authors.lastname: Chu
authors.forename: Nge
authors.initials: N
authors.lastname: Cheong
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Sheng-Hao
authors.initials: SH
authors.lastname: Chao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis*; D000090243:Nucleophosmin; D016601:RNA-Binding Proteins / Q000032:analysis; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
chemical_list: D000970:Antineoplastic Agents; C476123:HEXIM1 protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin