Activation of c-Myc confers resistance to venetoclax via inhibition of Bim in t(8;21)-positive acute myeloid leukemia

  • Cell Commun Signal. 2026 Jun 11. doi: 10.1186/s12964-026-02994-x.
Zhao Yin  #  1  2 ,  Zurong Yao  #  1  2 ,  DanDan Chen  #  1  2 ,  Dan Xu  1  2 ,  Li Xuan  1  2 ,  Qifa Liu  1  2 ,  Baohong Ping  3 ,  Guopan Yu  4  5  6
Affiliations
  • 1. Department of Hematology, Nanfang Hospital, Southern Medical University, No.1838, North of Guangzhou Avenue, Guangzhou City, Guangdong Province, 510515, China.
  • 2. Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou, Guangdong Province, 510515, China.
  • 3. Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, No.1838, North of Guangzhou Avenue, Guangzhou City, Guangdong Province, 510515, China. [email protected].
  • 4. Department of Hematology, Nanfang Hospital, Southern Medical University, No.1838, North of Guangzhou Avenue, Guangzhou City, Guangdong Province, 510515, China. [email protected].
  • 5. The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong Province, 510317, China. [email protected].
  • 6. Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou, Guangdong Province, 510515, China. [email protected].
  • # Contributed equally.
PMID: 42277819 DOI: 10.1186/s12964-026-02994-x
Abstract

Background and purpose: Venetoclax (VEN), a selective Bcl-2 Inhibitor, has improved outcomes in acute myeloid leukemia (AML). However, patients carrying the t(8;21)(q22;q22) translocation often show limited sensitivity to VEN-based therapy. This study aimed to elucidate the molecular mechanism of VEN resistance and explore rational combination strategies.

Experimental approach: Molecular and functional analyses were performed in t(8;21) AML models to examine the role of c-Myc activation in VEN response. Pharmacologic inhibition, genetic knockdown, and xenograft studies were used to assess the effects of c-Myc and its downstream effector Bim. The efficacy of VEN combined with homoharringtonine (HHT) was further evaluated.

Key results: VEN induced c-Myc expression in a dose-dependent manner, which was not suppressed by azacitidine. Inhibition or knockdown of c-Myc enhanced VEN-induced Apoptosis. Mechanistically, c-Myc repressed the pro-apoptotic BH3-only protein Bim, reducing mitochondrial priming and conferring VEN resistance. HHT downregulated c-Myc and restored Bim expression, leading to synergistic anti-leukemic activity with VEN in vitro and in vivo.

Conclusions and implications: c-Myc activation is a key driver of VEN resistance in t(8;21) AML. HHT acts as a mechanistically complementary agent, restoring VEN sensitivity. These results provide a preclinical rationale for clinical evaluation of VEN-HHT combination therapy in genetically defined AML subsets.

Keywords
Acute myeloid leukemia; Bim; Homoharringtonine; Venetoclax; c-Myc.
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