Page 165 - 2019_01-Haematologica-web

Plasma Cell Disorders
DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling
Kazuya Ishiguro,1,2 Hiroshi Kitajima,2 Takeshi Niinuma,2 Tadao Ishida,3
Reo Maruyama,4 Hiroshi Ikeda,1 Toshiaki Hayashi,1 Hajime Sasaki,1
Hideki Wakasugi,1 Koyo Nishiyama,2 Tetsuya Shindo,2 Eiichiro Yamamoto,1,2 Masahiro Kai,2 Yasushi Sasaki,5 Takashi Tokino,5 Hiroshi Nakase1
Ferrata Storti Foundation
Haematologica 2019 Volume 104(1):155-165
and Hiromu Suzuki2
1Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine; 2Department of Molecular Biology, Sapporo Medical University School of Medicine; 3Department of Hematology, Japanese Red Cross Medical Center, Tokyo; 4Project for Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo; 5Department of Medical Genome Sciences, Research Institute for Frontier Medicine and Sapporo Medical University School of Medicine, Japan
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 sur- vival. 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 immunoprecipita- tion-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 inhibi- tion upregulated genes associated with immune responses and interfer- on 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 devel- opment of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.
Introduction
Multiple myeloma (MM) is a genetically complex disorder caused by monoclonal proliferation of abnormal plasma cells. MM accounts for 1% of all cancers and 10% of hematologic malignancies in the United States, and there are 101,000 deaths per year caused by MM around the world.1 Despite development of a variety of new therapeutic agents, including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies and histone deacetylase inhibitors, MM remains an incur- able disorder.2
Epigenetic alterations such as aberrant DNA methylation and histone modifica- tion play key roles in the pathogenesis of MM and are thought to be potential ther- apeutic targets.3,4 For instance, the histone deacetylase (HDAC) inhibitor panobino- stat reportedly exerts synergistic anti-myeloma effects when combined with borte- zomib and dexamethasone, yielding a complete or near complete response in 27.6% of patients with relapsed or relapsed and refractory MM.5 Notably, HDAC inhibitors appear to affect a wide variety of non-histone proteins in addition to his- tones, exerting anti-myeloma effects that include upregulation of CDKN1A and dis- ruption of aggresomes.6 Methylation of histone lysine residues is a major epigenetic mechanism by which chromatin organization and gene expression are regulated.7 For instance, methylation of histone H3 lysine 4 (H3K4), H3K36 and H3K79 is asso-
Correspondence:
hsuzuki@sapmed.ac.jp
Received: February 15, 2018. Accepted: August 29, 2018. Pre-published: August 31, 2018.
doi:10.3324/haematol.2018.191262
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/155
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(1)
155
ARTICLE