MYC and CHK1 Dependent Cell Death in T-cell Lymphoma and Hodgkin Lymphoma Cell Lines and Human Xenograft Models Via Anti-Proteasomal Therapy (Illumina)

ABSTRACT: We examined the biological effects of a potent second-generation proteasome inhibitor, ixazomib, in T-cell lymphoma and Hodgkin lymphoma cell lines and human xenograft models. Ixazomib resulted in time- and dose-dependent cytotoxicity and apoptosis in all cell lines (IC50’s <75nM). In vivo studies via SCID tumor xenografts showed significant inhibition of tumor growth (P<0.001) with significantly improved survival (P<0.001) in Jurkat and L540 models with ixazomib-treated mice versus controls. Through global transcriptome and network analyses, ixazomib-treated Jurkat and L540 cells showed significant overlap in biological functions involved in regulation of cell cycle, chromatin modification, and DNA repair processes with a lack of conservation observed in a relatively ixazomib-resistant cell line, L428. Moreover, the predicted activation and inhibition status of tumor suppressors and oncogenes strongly favored ixazomib inhibition of tumor progression. Most notably, ixazomib down-regulated protein levels of MYC and its target genes. Additionally, chromatin immunoprecipitation showed that histone H3 acetylation affected MYC levels and cell death response to ixazomib. Furthermore, inhibition of MYC with JQ1 resulted in synergistic cell death in L428, which was confirmed utilizing MYC knockout. Collectively, ixazomib down-regulated MYC and downstream substrates in TCL and HL, while resistance appeared mediated through MYC- and CHK1-dependent mechanisms. L428 cells were treated with 25nM ixazomib for 24 hours, RNA was isolated using RNeasy Minikit (Qiagen), following instructions recommended supplied by the manufacturer. Purity and the yield of isolated RNA was determined using Bioanalyzer. These experiments were performed in biological triplicates. Microarray experiment with L428 was performed using Human HT 12 Genechip Illumina. Data for the L428 cell line was corrected through normalization of the housekeeping genes, quantile normalized, and then statistically relevant genes were determined with one-way ANOVA analysis with FDR <0.05.

ORGANISM(S): Homo sapiens

SUBMITTER: Afshin Beheshti 

PROVIDER: E-GEOD-66415 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress