2. Academic Validation
  3. BRD4 and MYB inhibition overcomes venetoclax resistance in EVI1-rearranged acute myeloid leukemia

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

  • Sci Rep. 2025 Oct 23;15(1):37099. doi: 10.1038/s41598-025-21034-1.
Weijia Zang # 1 2 3,  Yui Koike # 1 3,  Koutarou Nishimura 4 5,  Atsushi Tanaka 3 6,  Hiromi Yamazaki 1 3,  Takaya Yamasaki 1,  Hiromi Ito 1 3,  Yifan Zhang 1 2 3,  Yumi Aoyama 1 2 3,  Wataru Saika 1 3 7,  Muran Xiao 3,  Chihiro Hasegawa 1 3 8,  Hiroyoshi Kunimoto 9,  Hideaki Nakajima 9,  Fumihiko Ishikawa 10 11,  Akifumi Takaori-Kondo 2,  Daichi Inoue 12 13 14 15
Affiliations

Affiliations

  • 1 Department of Cancer Pathology, Graduate School of Medicine and Frontier Biosciences, The University of Osaka, Suita, 565-0871, Japan.
  • 2 Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 3 Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.
  • 4 Department of Cancer Pathology, Graduate School of Medicine and Frontier Biosciences, The University of Osaka, Suita, 565-0871, Japan. nishimura.koutarou.pww@osaka-u.ac.jp.
  • 5 Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan. nishimura.koutarou.pww@osaka-u.ac.jp.
  • 6 Department of Hematology, Kyoto-Katsura Hospital, Kyoto, Japan.
  • 7 Department of Hematology, Shiga University of Medical Science, Otsu, Japan.
  • 8 Department of Hematology and Oncology, Graduate School of Medicine, The University of Osaka, Suita, Japan.
  • 9 Department of Stem Cell and Immune Regulation, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
  • 10 Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
  • 11 RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 12 Department of Cancer Pathology, Graduate School of Medicine and Frontier Biosciences, The University of Osaka, Suita, 565-0871, Japan. inoue@patho.med.osaka-u.ac.jp.
  • 13 Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. inoue@patho.med.osaka-u.ac.jp.
  • 14 Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan. inoue@patho.med.osaka-u.ac.jp.
  • 15 Institute for Open and Transdisciplinary Research Initiatives, The University of Osaka, Suita, Japan. inoue@patho.med.osaka-u.ac.jp.
  • # Contributed equally.
PMID: 41131284 DOI: 10.1038/s41598-025-21034-1
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.

Keywords

Acute myeloid leukemia; BRD4; EVI1; Hypomethylating agent; MYB; Venetoclax.

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