Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia

• 成果类型: Article
• 署名作者: Wang, Jun-Yu; Gui, Tuan-Tuan; Jiao, Bo; Liu, Xuan; Ma, Xiao-Lin; Wang, Cheng; Qiao, Jing; Liu, Wei-Yang; Peng, Li-Jun; Rena, Jia-Yi; Zhua, Yong-Mei; Weng, Xiang-Qin; Wang, Chao; Zhang, Qian-Qian; Song, Gao-Xian; Dai, Yu- Ting; Wang, Zhen-Yi; Lv, Gang; Gao, Chen-Xu; Qiao, Niu; Zhang, Ming; Tan, Yun; Liu, Yuan- Fang; Wang, Sheng-Yue; Hou, Jian; Jing, Duo- Hui; Lyu, An-Kang; Mi, Jian-Qing; Chen, Zhu; Chen, Wen-Lian; Yin, Tong; Fang, Hai; Wang, Jin; Chen, Sai-Juan
• 署名单位: Shanghai Jiao Tong University; Chinese Academy of Medical Sciences - Peking Union Medical College; Chinese Academy of Sciences; Fudan University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai University of Traditional Chinese Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9010
• DOI: 10.1073/pnas.2423169122
• 发表日期: 2025-02-18
• 关键词: acute myeloid-leukemia; bile-acids; adolescents; resistance

摘要

Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age >= 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient- derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets. com/MALL), provide a framework for the metabolism- centered management of ALL.