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

IF 9.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-02-18 Epub Date: 2025-02-13 DOI:10.1073/pnas.2423169122
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
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引用次数: 0

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.

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来源期刊
CiteScore
19.00
自引率
0.90%
发文量
3575
审稿时长
2.5 months
期刊介绍: The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.
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