EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

Oncotarget
Taylor HardingBrian Van Ness

Abstract

Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation. Pre-treatment with EZH2 inhibitors greatly enhanced the sensitivity of HMCLs to the pan-HDAC inhibitor panobinostat in nearly all cases regardless of single agent EZH2 inhibitor sensitivity. Transcriptomic profiling revealed large-scale transcriptomic alteration by EZH2 inhibition highly enriched for cancer-related pathways. Combination treatment greatly increased the scale of gene expression change with a large portion of differentially expressed genes being unique to the combination. Transcriptomic analysis demonstrated that combination treatment further perturbed oncogenic pathways and signaling node...Continue Reading

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Citations

Mar 13, 2019·APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica·Konstantinos Dimopoulos, Kirsten Grønbaek
Dec 18, 2018·Biomarker Research·Rosemarie Tremblay-LeMayHong Chang
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May 7, 2021·The Application of Clinical Genetics·Hamza Hassan, Raphael Szalat
May 22, 2020·ACS Medicinal Chemistry Letters·Annalisa RomanelliSergio Valente

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Methods Mentioned

BETA
flow cytometry
RNA-seq
xenograft

Software Mentioned

R
Image J
Tophat2
Ingenuity Pathway Analysis ( IPA
Galaxy
Cufflinks
Cuffdiff
FASTQ
FastQC
IPA

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