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Background <p>Acute myeloid leukemia (AML) remains a therapeutic challenge due to drug resistance and relapse. Selinexor, an XPO1 inhibitor, shows limited efficacy as monotherapy, necessitating combination strategies. JQ1, a BET inhibitor targeting MYC, may synergize with Selinexor to enhance antileukemic effects.</p> Methods <p>AML cell lines, primary patient samples, and xenograft models (MLL-AF9, CDX, PDX) were treated with Selinexor and JQ1 alone or combined. Synergy was assessed via viability assays (Compusyn/SynergyFinder), apoptosis (flow cytometry/Western blot), and C-MYC suppression (qPCR/CRISPR). In vivo efficacy was evaluated by tumor burden (flow cytometry) and survival.</p> Results <p>The combination demonstrated strong synergy (CI &lt; 1, HSA &gt; 10) across AML models, with &gt; 80% inhibition in cell lines and primary samples. Mechanistically, it suppressed C-MYC (protein/mRNA), induced apoptosis (cleaved PARP), and arrested cell cycle. In vivo, the combination reduced leukemic burden in bone marrow, spleen, and liver, extending survival in xenografts. PDX models confirmed efficacy in primary AML cells.</p> Conclusions <p>Selinexor and JQ1 synergistically target AML by dual C-MYC inhibition, offering a promising strategy to overcome resistance. Further clinical evaluation is warranted.</p>

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Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C-MYC inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月8日

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  • Pei-Hong Wang,
  • Chu-Hong Hu,
  • Jia-Qi Fan,
  • Jia-Jun He,
  • Ting-Fen Deng,
  • Yan-Li Xu,
  • Yu-Jun Dai,
  • Shun-Qing Wang

摘要

Background

Acute myeloid leukemia (AML) remains a therapeutic challenge due to drug resistance and relapse. Selinexor, an XPO1 inhibitor, shows limited efficacy as monotherapy, necessitating combination strategies. JQ1, a BET inhibitor targeting MYC, may synergize with Selinexor to enhance antileukemic effects.

Methods

AML cell lines, primary patient samples, and xenograft models (MLL-AF9, CDX, PDX) were treated with Selinexor and JQ1 alone or combined. Synergy was assessed via viability assays (Compusyn/SynergyFinder), apoptosis (flow cytometry/Western blot), and C-MYC suppression (qPCR/CRISPR). In vivo efficacy was evaluated by tumor burden (flow cytometry) and survival.

Results

The combination demonstrated strong synergy (CI < 1, HSA > 10) across AML models, with > 80% inhibition in cell lines and primary samples. Mechanistically, it suppressed C-MYC (protein/mRNA), induced apoptosis (cleaved PARP), and arrested cell cycle. In vivo, the combination reduced leukemic burden in bone marrow, spleen, and liver, extending survival in xenografts. PDX models confirmed efficacy in primary AML cells.

Conclusions

Selinexor and JQ1 synergistically target AML by dual C-MYC inhibition, offering a promising strategy to overcome resistance. Further clinical evaluation is warranted.