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

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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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-02-13
DOI
https://doi.org/10.1073/pnas.2423169122
Citations
2
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
2.09

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article

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

Chenxu Gao, Q. L. Niu, Hai Fang, Yuanfang Liu et al.
2 citations
Proceedings of the National Academy of Sciences
Pancreatic and Hepatic Oncology Research
2.09
article

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

Chenxu Gao, Q. L. Niu, Hai Fang, Yuanfang Liu, Jun-Yu Wang, Zhenyi Wang, Duohui Jing, Cheng Wang, Yuting Dai, Tuantuan Gui, Jing Qiao, Wen‐Lian Chen, Yun Tan, Shengyue Wang, Xuan Liu, Yongmei Zhu, Jin Wang, Qian-Qian Zhang, Chao Wang, Ming Zhang, Gang Lv, Bo Jiao, Yin Tong, Weiyang Liu, Jiayi Ren, Xiaolin Ma, Lijun Peng, Ankang Lyu, Jian‐Qing Mi, Zhu Chen, Jian Hou, Sai‐Juan Chen, Gaoxian Song, Xiang-Qin Weng
article en
2 citations

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.

Proceedings of the National Academy of SciencesVol. 122(7)
Shanghai Jiao Tong University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Renji Hospital (CN), Ruijin Hospital (CN), Fudan University Shanghai Cancer Center (CN), Shanghai University of Traditional Chinese Medicine (CN), Longhua Hospital Shanghai University of Traditional Chinese Medicine (CN), Shanghai Institute of Hematology (CN)
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 Percentile: Top 14%
Pancreatic and Hepatic Oncology Research
2.09
DOIOpen Access PDFOpenAlex
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