DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling

Haematologica
Kazuya IshiguroHiromu Suzuki

Abstract

Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. DOT1L expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation in vitro The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower IRF4/MYC expression were less sensitive to DOT1L inhibition, but with prolonged treatment, anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of mul...Continue Reading

Citations

Nov 9, 2019·Future Medicinal Chemistry·Saurabh Loharch, Raman Parkesh
Jul 17, 2020·Frontiers in Oncology·Anthony QuaglianoSonali P Barwe
Aug 21, 2020·Nature Communications·R VatapalliS A Abdulkadir
Apr 10, 2019·Expert Opinion on Investigational Drugs·Shirong LiKlaus Podar
Jun 22, 2021·Frontiers in Pharmacology·Wen-Min ZhouJian-Ye Zhang
Aug 31, 2021·RSC Chemical Biology·Robert B A Quinlan, Paul E Brennan

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Methods Mentioned

BETA
xenograft
flow cytometry
ChIP-seq
ChIP
ChIP-PCR

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