Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics PMID: 42362999

GLP-1 and Obesity Research

2026-08-18

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

Nat Cancer. 2026 Jun;7(6):944-963. doi: 10.1038/s43018-026-01184-5.

Xin He ^# ¹ , Lei Zhang ^# ¹ , Yang Li ^# ¹ ² , Song-Bai Liu ^# ³ , Zheng Li ^# ⁴ ⁵ , Haojie Dong ¹ , Genevieve E Baker ⁶ , Le Xuan Truong Nguyen ¹ , Wei Chen ⁷ , Jinhui Wang ⁷ , Zhilian Jia ⁸ , Xiyuan Lu ⁹ , Yi-Chun Lin ¹⁰ , Zunsong Hu ⁸ , Umesh Prasad Yadav ¹ , Meng Liu ¹ , Lianjun Zhang ¹ , Zhenhua Chen ⁸ , Xiwei Wu ⁷ , Jianjun Chen ⁸ , Chun-Wei Chen ⁸ , Stefano Tiziani ⁹ , Weidong Hu ¹¹ , Ya-Huei Kuo ¹ , Sheng-Li Xue ⁴ ⁵ , Yong Zhang ¹² , Min Li ¹³ , Yaoqiu Zhu ¹⁰ , Guido Marcucci ¹ , Zhaohui Gu ⁸ , J Jefferson P Perry ⁶ , Yun Lyna Luo ¹⁰ , Ling Li ¹⁴

Affiliations

1. Department of Hematological Malignancies Translational Science, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
2. Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
3. Suzhou Key Laboratory of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, China.
4. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
5. Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
6. Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
7. Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
8. Department of Computational and Quantitative Medicine & Systems Biology, City of Hope Medical Center, Duarte, CA, USA.
9. Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.
10. College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
11. Department of Immunology and Theranostics, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
12. Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
13. Division of Biostatistics, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
14. Department of Hematological Malignancies Translational Science, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA. [email protected].
# Contributed equally.

Abstract

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.