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Background <p>Acute myeloid leukemia (AML) remains challenging due to chemotherapy resistance and disease relapse. Investigating novel regulators of AML pathogenesis and drug sensitivity is crucial for improving outcomes. Myocyte enhancer factor 2&#xa0;A (MEF2A) was selected for this study based on its potential role in oncogenic pathways and the unmet need to understand its impact on AML progression and doxorubicin (DOX) chemoresistance.</p> Methods <p>Bioinformatics analysis of the GSE245305 dataset was used to identify the differentially expressed genes between AML and normal samples. MEF2A and zDHHC palmitoyltransferase 20 (ZDHHC20) mRNA expression was validated using quantitative real-time PCR (qRT-PCR). Western blotting and immunohistochemistry (IHC) assays were performed to analyze protein expression. Functional assays were performed to analyze cell viability, proliferation, apoptosis, and glucose metabolism. Mechanistic studies involved dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to validate the association of MEF2A and ZDHHC20. A xenograft mouse model was used to assess the effect of MEF2A knockdown on tumor sensitivity to DOX.</p> Results <p>MEF2A exhibited upregulated expression in AML samples in comparison with healthy samples. Its knockdown suppressed proliferation, glycolysis (reducing glucose uptake, lactate production, and ATP levels), and tumor growth, while increasing apoptosis and DOX sensitivity in AML cells. Critically, MEF2A transcriptionally activated ZDHHC20 in HL-60 and KG-1 cells. ZDHHC20 overexpression reversed the antitumor effects of MEF2A silencing, promoting malignancy and DOX resistance. Mechanistically, MEF2A depletion inactivated the nuclear factor kappa B (NF-κB) pathway via ZDHHC20 downregulation. In vivo, MEF2A knockdown significantly enhanced the sensitivity of AML xenografts to DOX treatment.</p> Conclusion <p>MEF2A promoted AML progression and DOX resistance by transcriptionally upregulating ZDHHC20, thereby activating the NF-κB pathway. Targeting the MEF2A/ZDHHC20 axis represents a promising therapeutic strategy to overcome chemoresistance and improve clinical outcomes in AML patients.</p>

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MEF2A activates the ZDHHC20/NF-κB pathway to inhibit doxorubicin sensitivity and promote the malignant progression of acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月26日

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  • Xi Ming,
  • Wanying Liu,
  • Jiaying Wu,
  • Sijia Yan,
  • Shuai Su,
  • Yu Wang,
  • Rubing Zheng,
  • Yi Xiao

摘要

Background

Acute myeloid leukemia (AML) remains challenging due to chemotherapy resistance and disease relapse. Investigating novel regulators of AML pathogenesis and drug sensitivity is crucial for improving outcomes. Myocyte enhancer factor 2 A (MEF2A) was selected for this study based on its potential role in oncogenic pathways and the unmet need to understand its impact on AML progression and doxorubicin (DOX) chemoresistance.

Methods

Bioinformatics analysis of the GSE245305 dataset was used to identify the differentially expressed genes between AML and normal samples. MEF2A and zDHHC palmitoyltransferase 20 (ZDHHC20) mRNA expression was validated using quantitative real-time PCR (qRT-PCR). Western blotting and immunohistochemistry (IHC) assays were performed to analyze protein expression. Functional assays were performed to analyze cell viability, proliferation, apoptosis, and glucose metabolism. Mechanistic studies involved dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to validate the association of MEF2A and ZDHHC20. A xenograft mouse model was used to assess the effect of MEF2A knockdown on tumor sensitivity to DOX.

Results

MEF2A exhibited upregulated expression in AML samples in comparison with healthy samples. Its knockdown suppressed proliferation, glycolysis (reducing glucose uptake, lactate production, and ATP levels), and tumor growth, while increasing apoptosis and DOX sensitivity in AML cells. Critically, MEF2A transcriptionally activated ZDHHC20 in HL-60 and KG-1 cells. ZDHHC20 overexpression reversed the antitumor effects of MEF2A silencing, promoting malignancy and DOX resistance. Mechanistically, MEF2A depletion inactivated the nuclear factor kappa B (NF-κB) pathway via ZDHHC20 downregulation. In vivo, MEF2A knockdown significantly enhanced the sensitivity of AML xenografts to DOX treatment.

Conclusion

MEF2A promoted AML progression and DOX resistance by transcriptionally upregulating ZDHHC20, thereby activating the NF-κB pathway. Targeting the MEF2A/ZDHHC20 axis represents a promising therapeutic strategy to overcome chemoresistance and improve clinical outcomes in AML patients.