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<p>De novo purine synthesis is required to maintain tumor growth; however, its impact on therapy resistance remains unclear. Here, through a dynamic BH3-priming-based CRISPR screen, we found that deletion of <i>ADSS2</i>, which encodes the adenylosuccinate synthase 2 enzyme essential for adenosine monophosphate (AMP) synthesis, re-sensitizes drug-resistant acute myeloid leukemia cells to venetoclax and a myeloid cell leukemia-1 (MCL1) inhibitor. Single-cell sequencing analysis of patient-derived xenograft samples revealed a positive association of high ADSS2 activity in <i>TP53</i>-mutant cells with poor responsiveness to venetoclax. We developed an ADSS2 antagonist, which synergized with BH3 mimetics to promote apoptosis in preclinical models. Mechanistically, sensitization mediated by ADSS2 targeting correlated with downregulated AMP-activated protein kinase activity, which in resistant cells promotes mitophagy to eliminate damaged mitochondria after BH3 mimetic treatment. These data show that AMP synthesis promotes BH3 mimetic resistance and that combining ADSS2 targeting with BH3 mimetics represents a promising anti-cancer approach.</p>

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Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics

  • 期刊论文

  • 发表日期：

    2026年6月26日

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  • Xin He,
  • Lei Zhang,
  • Yang Li,
  • Song-Bai Liu,
  • Zheng Li,
  • Haojie Dong,
  • Genevieve E. Baker,
  • Le Xuan Truong Nguyen,
  • Wei Chen,
  • Jinhui Wang,
  • Zhilian Jia,
  • Xiyuan Lu,
  • Yi-Chun Lin,
  • Zunsong Hu,
  • Umesh Prasad Yadav,
  • Meng Liu,
  • Lianjun Zhang,
  • Zhenhua Chen,
  • Xiwei Wu,
  • Jianjun Chen,
  • Chun-Wei Chen,
  • Stefano Tiziani,
  • Weidong Hu,
  • Ya-Huei Kuo,
  • Sheng-Li Xue,
  • Yong Zhang,
  • Min Li,
  • Yaoqiu Zhu,
  • Guido Marcucci,
  • Zhaohui Gu,
  • J. Jefferson P. Perry,
  • Yun Lyna Luo,
  • Ling Li

摘要

De novo purine synthesis is required to maintain tumor growth; however, its impact on therapy resistance remains unclear. Here, through a dynamic BH3-priming-based CRISPR screen, we found that deletion of ADSS2, which encodes the adenylosuccinate synthase 2 enzyme essential for adenosine monophosphate (AMP) synthesis, re-sensitizes drug-resistant acute myeloid leukemia cells to venetoclax and a myeloid cell leukemia-1 (MCL1) inhibitor. Single-cell sequencing analysis of patient-derived xenograft samples revealed a positive association of high ADSS2 activity in TP53-mutant cells with poor responsiveness to venetoclax. We developed an ADSS2 antagonist, which synergized with BH3 mimetics to promote apoptosis in preclinical models. Mechanistically, sensitization mediated by ADSS2 targeting correlated with downregulated AMP-activated protein kinase activity, which in resistant cells promotes mitophagy to eliminate damaged mitochondria after BH3 mimetic treatment. These data show that AMP synthesis promotes BH3 mimetic resistance and that combining ADSS2 targeting with BH3 mimetics represents a promising anti-cancer approach.