Peposertib suppresses generation of FLT3-internal tandem duplication formed by contralateral double nicks

Yoshida, Shota; Onozawa, Masahiro; Yokoyama, Shota; Matsukawa, Toshihiro; Goto, Hideki; Hirabayashi, Shinsuke; Kondo, Takeshi; Hashimoto, Daigo; Onodera, Yasuhito; Teshima, Takanori

Peposertib suppresses generation of FLT3-internal tandem duplication formed by contralateral double nicks

Yoshida, Shota; Onozawa, Masahiro; Yokoyama, Shota et al.

Experimental Hematology, 2025, 149, 104819

Permalink : https://hdl.handle.net/2115/97998

このアイテムのアクセス数:28件（2026-08-11 11:25 集計）

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論文情報

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アクセス権	open access
URI	https://hdl.handle.net/2115/97998
タイトル	Peposertib suppresses generation of FLT3-internal tandem duplication formed by contralateral double nicks
著者	Yoshida, Shota ; Onozawa, Masahiro ; Yokoyama, Shota ; Matsukawa, Toshihiro ; Goto, Hideki ; Hirabayashi, Shinsuke ; Kondo, Takeshi ; Hashimoto, Daigo ; Onodera, Yasuhito ; Teshima, Takanori
著者名 Yoshida, Shota
e-Rad_Researcher 70455632 著者名 Onozawa, Masahiro
著者名 Yokoyama, Shota
e-Rad_Researcher 20963169 著者名 Matsukawa, Toshihiro
e-Rad_Researcher 70759290 著者名 Goto, Hideki
e-Rad_Researcher 50769635 著者名 Hirabayashi, Shinsuke
著者名 Kondo, Takeshi
e-Rad_Researcher 20419576 著者名 Hashimoto, Daigo
e-Rad_Researcher 90435561 著者名 Onodera, Yasuhito
e-Rad_Researcher 40284096 著者名 Teshima, Takanori
言語	英語
キーワード	FLT3-ITD
	Acute myeloid leukemia
	Double-strand break
	CRISPR/Cas9
	Non-homologous end joining
	Peposertib
発行日	2025-05-31
出版者	Elsevier
収録物名	Experimental Hematology
巻(号)	149
ページ	104819
抄録	Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is the most frequent gene mutation in acute myeloid leukemia. The consequences of FLT3-ITD have been analyzed in detail; however, the molecular mechanisms underlying the generation of FLT3-ITD remain to be elucidated. We analyzed FLT3-ITDs in clinical samples using deep sequencing and identified not only oligoclonal ITDs but also rare deletion clones clustered at the palindrome-like sequence at FLT3 exon 14. We hypothesized that FLT3 exon 14 is genetically unstable due to the palindrome-like sequence at the region and that genomic damage at the site initiates FLT3-ITD formation. We used clustered regularly interspaced short palindromic repeats (CRISPR)/ Cas9 to induce DNA damage for creating artificial FLT3-ITDs in human and mouse cell lines. We found that double nicks on the adjacent contralateral strand most efficiently generate ITDs. The artificial ITDs resembled clinical ITDs in the length distribution and characteristics at the joint. We further compared the inhibitory effects of olaparib and peposertib, specific inhibitors of single-strand break (SSB) and double-strand break (DSB) repair, respectively. Peposertib remarkably reduced ITD formation, but olaparib did not affect the mutation pattern. The findings indicated that nonhomologous end joining has a crucial role in the generation of ITDs. Our data shed light to the new role of peposertib, which potentially suppresses the generation of de novo FLT3-ITDs caused by mis-repair events of the DNA damages in a clinical course.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
権利情報	© 2025. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
PISSN	0301-472X
関連情報	PMID 40456437
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1016/j.exphem.2025.104819