BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia

Zang, Weijia; Koike, Yui; Nishimura, Koutarou; Tanaka, Atsushi; Yamazaki, Hiromi; Yamasaki, Takaya; Ito, Hiromi; Zhang, Yifan; Aoyama, Yumi; Saika, Wataru; Xiao, Muran; Hasegawa, Chihiro; Kunimoto, Hiroyoshi; Nakajima, Hideaki; Ishikawa, Fumihiko; Takaori-Kondo, Akifumi; Inoue, Daichi

doi:https://doi.org/10.1038/s41598-025-21034-1

BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia

Zang, Weijia; Koike, Yui; Nishimura, Koutarou et al.

Scientific Reports, 2025, 15, 37099

アクセス数:203件（2026-02-16 16:45 集計）

固定URL: https://hdl.handle.net/11094/103499

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タイトル	BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia
著者	著者名 Zang, Weijia
	NRID 1000030644942 1000030644942 ORCID 0000-0002-4470-6350 0000-0002-4470-6350 researchmap permalink yuikoike yuikoike Scopus Author ID 57859520900 57859520900 著者名 Koike, Yui
	NRID 1000030909982 1000030909982 researchmap permalink wf7iuSFsDY5XqBhN wf7iuSFsDY5XqBhN 著者名 Nishimura, Koutarou
	著者名 Tanaka, Atsushi
	NRID 1000020720915 1000020720915 researchmap permalink hiromiyamazaki hiromiyamazaki Scopus Author ID 59112159900 59112159900 著者名 Yamazaki, Hiromi
	researchmap permalink takaya.yamasaki takaya.yamasaki Scopus Author ID 60152324000 60152324000 著者名 Yamasaki, Takaya
	著者名 Ito, Hiromi
	著者名 Zhang, Yifan
	著者名 Aoyama, Yumi
	著者名 Saika, Wataru
	著者名 Xiao, Muran
	著者名 Hasegawa, Chihiro
	NRID 1000080464923 1000080464923 著者名 Kunimoto, Hiroyoshi
	NRID 1000030217723 1000030217723 著者名 Nakajima, Hideaki
	NRID 1000030403918 1000030403918 著者名 Ishikawa, Fumihiko
	NRID 1000020324626 1000020324626 著者名 Takaori-Kondo, Akifumi
	NRID 1000080735746 1000080735746 researchmap permalink nekosuke nekosuke 著者名 Inoue, Daichi
キーワード等	Acute myeloid leukemia
	BRD4
	EVI1
	Hypomethylating agent
	MYB
	Venetoclax
内容	Zang W., Koike Y., Nishimura K., et al. BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia. Scientific Reports 15, 37099 (2025); https://doi.org/10.1038/s41598-025-21034-1.
抄録	EVI1-rearranged acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21q26) represents a distinct and aggressive subtype characterized by poor prognosis and limited treatment options. However, the optimal strategy to overcome resistance to conventional therapy remains elusive. Building upon observations correlating EVI1 overexpression with reduced sensitivity to venetoclax, a BH3-mimetic BCL-2 inhibitor, we investigated the mechanisms of resistance to venetoclax in combination with hypomethylating agents in inv(3)/t(3;3) AML cells. Utilizing novel murine models recapitulating inv(3) AML with concomitant SF3B1 mutations, we conducted comprehensive phenotypic and transcriptomic analyses in the presence or absence of venetoclax-containing therapy. Despite initial therapeutic responses, manifested as partially prolonged survival and myeloid differentiation, resistant leukemic cells demonstrated enhanced dependency on BRD4 and MYB pathways with a dormant phenotype. Notably, inhibition of either BRD4 or MYB significantly augmented the efficacy of venetoclax and hypomethylating agents in both murine and patient-derived AML models harboring inv(3) and SF3B1 mutations. These findings elucidate the transcriptional dynamics underlying venetoclax resistance and propose alternative therapeutic strategies targeting BRD4 and MYB as promising avenues for improving outcomes in patients with EVI1-rearranged AML. Our work highlights the necessity for innovative combination therapies to address the multifaceted mechanisms of resistance in this high-risk leukemia subtype.
出版者	Nature Research
収録物名	Scientific Reports
巻(号)	15
ページ	37099
刊行年月	2025-10-23
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103499
eISSN	20452322
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1038/s41598-025-21034-1
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Scientific Reports. 2025, 15, p. 37099
DC.title	BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia
DC.creator	Zang, Weijia
	Koike, Yui
	Nishimura, Koutarou
	Tanaka, Atsushi
	Yamazaki, Hiromi
	Yamasaki, Takaya
	Ito, Hiromi
	Zhang, Yifan
	Aoyama, Yumi
	Saika, Wataru
	Xiao, Muran
	Hasegawa, Chihiro
	Kunimoto, Hiroyoshi
	Nakajima, Hideaki
	Ishikawa, Fumihiko
	Takaori-Kondo, Akifumi
	Inoue, Daichi
DC.publisher	Nature Research
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-10-23
DC.identifier	https://doi.org/10.1038/s41598-025-21034-1
DC.subject	Acute myeloid leukemia
	BRD4
	EVI1
	Hypomethylating agent
	MYB
	Venetoclax
DC.description	Zang W., Koike Y., Nishimura K., et al. BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia. Scientific Reports 15, 37099 (2025); https://doi.org/10.1038/s41598-025-21034-1.
DCTERMS.abstract	EVI1-rearranged acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21q26) represents a distinct and aggressive subtype characterized by poor prognosis and limited treatment options. However, the optimal strategy to overcome resistance to conventional therapy remains elusive. Building upon observations correlating EVI1 overexpression with reduced sensitivity to venetoclax, a BH3-mimetic BCL-2 inhibitor, we investigated the mechanisms of resistance to venetoclax in combination with hypomethylating agents in inv(3)/t(3;3) AML cells. Utilizing novel murine models recapitulating inv(3) AML with concomitant SF3B1 mutations, we conducted comprehensive phenotypic and transcriptomic analyses in the presence or absence of venetoclax-containing therapy. Despite initial therapeutic responses, manifested as partially prolonged survival and myeloid differentiation, resistant leukemic cells demonstrated enhanced dependency on BRD4 and MYB pathways with a dormant phenotype. Notably, inhibition of either BRD4 or MYB significantly augmented the efficacy of venetoclax and hypomethylating agents in both murine and patient-derived AML models harboring inv(3) and SF3B1 mutations. These findings elucidate the transcriptional dynamics underlying venetoclax resistance and propose alternative therapeutic strategies targeting BRD4 and MYB as promising avenues for improving outcomes in patients with EVI1-rearranged AML. Our work highlights the necessity for innovative combination therapies to address the multifaceted mechanisms of resistance in this high-risk leukemia subtype.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	103499
citation_title	BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia
citation_author	Zang, Weijia
	Koike, Yui
	Nishimura, Koutarou
	Tanaka, Atsushi
	Yamazaki, Hiromi
	Yamasaki, Takaya
	Ito, Hiromi
	Zhang, Yifan
	Aoyama, Yumi
	Saika, Wataru
	Xiao, Muran
	Hasegawa, Chihiro
	Kunimoto, Hiroyoshi
	Nakajima, Hideaki
	Ishikawa, Fumihiko
	Takaori-Kondo, Akifumi
	Inoue, Daichi
citation_publisher	Nature Research
citation_language	英語
citation_date	2025-10-23
citation_journal_title	Scientific Reports
citation_volume	15
citation_firstpage	37099
citation_doi	https://doi.org/10.1038/s41598-025-21034-1
citation_public_url	https://hdl.handle.net/11094/103499

BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia

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