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Title: Endogenous APOBEC3B Overexpression Constitutively Generates DNA Substitutions and Deletions in Myeloma Cells
Authors: Yamazaki, Hiroyuki
Shirakawa, Kotaro  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-7469-1276 (unconfirmed)
Matsumoto, Tadahiko
Hirabayashi, Shigeki
Murakawa, Yasuhiro  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-5415-1352 (unconfirmed)
Kobayashi, Masayuki
Sarca, Anamaria Daniela
Kazuma, Yasuhiro
Matsui, Hiroyuki
Maruyama, Wataru
Fukuda, Hirofumi
Shirakawa, Ryutaro
Shindo, Keisuke
Ri, Masaki
Iida, Shinsuke
Takaori-Kondo, Akifumi
Author's alias: 山崎, 寛章
白川, 康太郎
松本, 忠彦
平林, 茂樹
村川, 泰裕
小林, 正行
数馬, 安浩
松井, 宏行
丸山, 亙
福田, 寛文
白川, 龍太郎
新堂, 啓祐
李, 正樹
飯田, 真介
高折, 晃史
Keywords: Myeloma
Oncogenes
Issue Date: 9-May-2019
Publisher: Springer Science and Business Media LLC
Journal title: Scientific Reports
Volume: 9
Thesis number: 7122
Abstract: Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) DNA cytosine deaminases have emerged as potential genomic mutators in various cancers. Multiple myeloma accumulates APOBEC signature mutations as it progresses; however, the mechanisms underlying APOBEC signature acquisition and its consequences remain elusive. In this study, we examined the significance and clinical impact of APOBEC3B (A3B) activity in multiple myeloma. Among APOBECs, only highly expressed A3B was associated with poor prognosis in myeloma patients, independent of other known poor prognostic factors. Quantitative PCR revealed that CD138-positive primary myeloma cells and myeloma cell lines exhibited remarkably high A3B expression levels. Interestingly, lentiviral A3B knockdown prevented the generation of deletion and loss-of-function mutations in exogenous DNA, whereas in control cells, these mutations accumulated with time. A3B knockdown also decreased the basal levels of γ-H2AX foci, suggesting that A3B promotes constitutive DNA double-strand breaks in myeloma cells. Importantly, among control shRNA-transduced cells, we observed the generation of clones that harboured diverse mutations in exogenous genes and several endogenous genes frequently mutated in myeloma, including TP53. Taken together, the results suggest that A3B constitutively mutates the tumour genome beyond the protection of the DNA repair system, which may lead to clonal evolution and genomic instability in myeloma.
Description: 多発性骨髄腫における遺伝子変異蓄積の分子メカニズムの一端を解明 --新たな治療標的としてのDNAシトシン脱アミノ化酵素の可能性--. 京都大学プレスリリース. 2019-05-17.
Rights: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
URI: http://hdl.handle.net/2433/241387
DOI(Published Version): 10.1038/s41598-019-43575-y
PubMed ID: 31073151
Related Link: https://www.kyoto-u.ac.jp/ja/research-news/2019-05-17
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