A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis

Cheng Yu Tsai, Toshie Saito, Mayur Sarangdhar, Maisam Abu-El-Haija, Li Wen, Bomi Lee, Mang Yu, Den A. Lipata, Murli Manohar, Monique T. Barakat, Kévin Contrepois, Thai Hoa Tran, Yves Theoret, Na Bo, Ying Ding, Kristen Stevenson, Elena J. Ladas, Lewis B. Silverman, Loredana Quadro, Tracy G. AnthonyAnil G. Jegga, Sohail Z. Husain

Research output: Contribution to journalArticlepeer-review


Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

Original languageEnglish (US)
Article numbereabn2110
JournalScience translational medicine
Issue number687
StatePublished - Mar 15 2023

All Science Journal Classification (ASJC) codes

  • Medicine(all)


Dive into the research topics of 'A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis'. Together they form a unique fingerprint.

Cite this