Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia
Year: 2025
Type: article
Abstract: 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.
Authors: Jun-Yu Wang, Tuan-Tuan Gui, Bo Jiao, Xuan Liu, Xiao-Lin Ma, Cheng Wang, Jing Qiao, Wei-Yang Liu, Li-Jun Peng, Jia-Yi Ren, Yong-Mei Zhu, Xiang-Qin Weng, Chao Wang, Qian-Qian Zhang, Gao-Xian Song, Yu-Ting Dai, Zhen-Yi Wang, Gang Lv, Chen-Xu Gao, Niu Qiao, Ming Zhang, Yun Tan, Yuan-Fang Liu, Sheng-Yue Wang, Jian Hou, Duo-Hui Jing, An-Kang Lyu, Jian-Qing Mi, Zhu Chen, Wen-Lian Chen, Tong Yin, Hai Fang, Jin Wang, Sai-Juan Chen
Institutions: Shanghai Medical College of Fudan University, Shanghai Jiao Tong University, Chinese Academy of Medical Sciences & Peking Union Medical College, Ruijin Hospital, Fudan University Shanghai Cancer Center, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Renji Hospital, Longhua Hospital Shanghai University of Traditional Chinese Medicine
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Innovative Research Team of High-level Local University in Shanghai, Samuel Waxman Cancer Research Foundation, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, National Key Research and Development Program of China, Overseas Expertise Introduction Project for Discipline Innovation
OpenAlex ID: W4407447209