A lipid-immune network signature defines susceptibility to asparaginase-associated pancreatitis
Cheng-Yu Tsai, Na Bo, Thai Hoa Tran, Maisam Abu-El-Haija, Gayathri Swaminathan, Bomi Lee, Sudhir Ghandikota, Li Wen, Yves Théorêt, Steven D. Mittelman, Elena J. Ladas, Anil G. Jegga, Lewis B. Silverman, Ying Ding, Sohail Z. Husain
Cheng-Yu Tsai, Na Bo, Thai Hoa Tran, Maisam Abu-El-Haija, Gayathri Swaminathan, Bomi Lee, Sudhir Ghandikota, Li Wen, Yves Théorêt, Steven D. Mittelman, Elena J. Ladas, Anil G. Jegga, Lewis B. Silverman, Ying Ding, Sohail Z. Husain
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Clinical Research and Public Health Gastroenterology Hematology Oncology

A lipid-immune network signature defines susceptibility to asparaginase-associated pancreatitis

Abstract

BACKGROUND Asparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP.METHODS We performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses and integrated lipid-cytokine associations using proteomics.RESULTS Across cohorts, we identified a reproducible lysophosphatidylcholine-centered (LPC-centered) signature characterized by attenuated induction therapy–associated LPC responses and disruption of LPC coregulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid-cytokine coupling, including a flip in association direction for LPC species and IL-18 between cases and controls. Although IL-18/LPC ratios did not differ globally, elevated postinduction IL-18/LPC ratios identified AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81).CONCLUSION These findings support a systems-level model in which failure of coordinated lipid-immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies.TRIAL REGISTRATION NCT00400946; NCT01574274; NCT03020030 (parent trials).FUNDING Servier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Québec – Santé; Fondation Charles-Bruneau; Leukemia & Lymphoma Society of Canada.

Authors

Cheng-Yu Tsai, Na Bo, Thai Hoa Tran, Maisam Abu-El-Haija, Gayathri Swaminathan, Bomi Lee, Sudhir Ghandikota, Li Wen, Yves Théorêt, Steven D. Mittelman, Elena J. Ladas, Anil G. Jegga, Lewis B. Silverman, Ying Ding, Sohail Z. Husain

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Figure 1

Global lipidomic landscape across induction therapy in the discovery cohort.

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Global lipidomic landscape across induction therapy in the discovery coh...
(A) Study schematic for the discovery cohort, showing prospective plasma sample collection at 2 time points: an initial pre-asparaginase time point and a postinduction time point following exposure to asparaginase-containing induction therapy. (B) Overview of the plasma lipidome measured using the Metabolon Complex Lipid Panel, comprising 3 major lipid groups (neutral lipids, phospholipids, sphingolipids) and 14 lipid classes. (C) Number and proportion of lipid species detected within each lipid class and group after quality filtering. (D) Box-and-whisker plots showing the distribution of lipid class concentrations across all samples, demonstrating expected dominance of cholesteryl esters, triacylglycerols, phosphatidylcholines, and sphingomyelins in human plasma. (E) PCA illustrating a strong separation between initial and postinduction samples when cases and controls are combined, indicating a global lipidomic shift during induction therapy. (F) Comparison of lipid class concentrations between initial and postinduction time points, highlighting increased dispersion and dynamic range postinduction. (G) PCA stratified by case-control status at each time point shows minimal separation at baseline but modest divergence postinduction. (H) Lipid class–level comparisons between cases and controls reveal selective postinduction reductions in lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and cholesteryl ester (CE) among cases. *P < 0.05, **P < 0.01; unpaired 2-tailed t test with Welch’s correction. The discovery cohort includes 26 cases and 26 controls. Unless otherwise indicated, analyses include all available samples from these participants at each time point. For all box-and-whisker plots (D, F, and H), center line = median; box = IQR; whiskers = min–max.