Asparaginase is an integral part of the treatment for acute lymphoblastic leukemia, the most common childhood cancer. Asparaginase produces hepatotoxicity resulting in treatment-related metabolic complications that include fatty liver, reduced plasma proteins, and coagulation problems that lead to thromboembolism and cerebrovascular events. Our long-term goal is to increase the safety and efficacy of asparaginase. The objective of this proposal is to discover mechanisms by which asparaginase causes adverse metabolic effects. To accomplish this, we propose to identify key molecular events that modulate hepatic dysfunction by asparaginase. Our preliminary data demonstrate that asparaginase increases phosphorylation of the translation factor, eIF2, by GCN2. Deletion of GCN2 precludes adaptive responses to asparaginase and enhances endoplasmic reticulum (ER) stress, leading to induction of another eIF2 kinase called PKR-like ER- resident Kinase (PERK). The central hypothesis is that activation of eIF2 kinases prevent and/or mitigate hepatic dysfunction by asparaginase. We plan to test our hypothesis and accomplish the objective of this application by pursuing the following specific aims:
Aim 1) Identify the role of GCN2 in liver during asparaginase treatment;
Aim 2) Determine the role of PERK in liver during asparaginase treatment;
Aim 3) Characterize age differences in eIF2 kinase signaling in liver by asparaginase. To accomplish the above aims, asparaginase will be administered to both wild-type mice and mice deleted for the eIF2 kinases, GCN2 and/or PERK. Time course analysis will focus on how modulation of eIF2 kinase signaling and activation of ER stress relates to development of liver dysfunction. In addition, asparaginase will be administered to mice of varying ages and key molecular and metabolic responses to asparaginase will be assessed. This proposal is innovative in that it seeks to identify the progression of molecular events that lead to liver dysfunction by asparaginase at different ages. The work proposed is significant as it will help identify pediatric patients at risk for adverse metabolic events by asparaginase during the developmental continuum. The results will also be used to develop and test new methods of prevention and/or treatment.

Public Health Relevance

The proposed project is relevant to public health as it seeks to improve the treatment regimen for acute lymphoblastic leukemia, the most common childhood cancer. This proposal aims to reduce and prevent adverse metabolic events caused by asparaginase by identifying the molecular events that cause liver dysfunction.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-K (10))
Program Officer
Taylor-Zapata, Perdita
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rutgers University
Schools of Earth Sciences/Natur
New Brunswick
United States
Zip Code
Nikonorova, Inna A; Mirek, Emily T; Signore, Christina C et al. (2018) Time-resolved analysis of amino acid stress identifies eIF2 phosphorylation as necessary to inhibit mTORC1 activity in liver. J Biol Chem 293:5005-5015
Al-Baghdadi, Rana J T; Nikonorova, Inna A; Mirek, Emily T et al. (2017) Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase. Sci Rep 7:1272
Nikonorova, Inna A; Al-Baghdadi, Rana J T; Mirek, Emily T et al. (2017) Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice. J Biol Chem 292:6786-6798
Pettit, Ashley P; Jonsson, William O; Bargoud, Albert R et al. (2017) Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice. J Nutr 147:1031-1040
Anthony, T G (2016) Mechanisms of protein balance in skeletal muscle. Domest Anim Endocrinol 56 Suppl:S23-32
Fusakio, Michael E; Willy, Jeffrey A; Wang, Yongping et al. (2016) Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol Biol Cell 27:1536-51
Wanders, Desiree; Stone, Kirsten P; Forney, Laura A et al. (2016) Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. Diabetes 65:1499-510
Phillipson-Weiner, Lindsey; Mirek, Emily T; Wang, Yongping et al. (2016) General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 310:G1061-70
Wilson, Gabriel J; Lennox, Brittany A; She, Pengxiang et al. (2015) GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment. Am J Physiol Endocrinol Metab 308:E283-93
Tuazon, Marc A; McConnell, Taylor R; Wilson, Gabriel J et al. (2015) Intensity-dependent and sex-specific alterations in hepatic triglyceride metabolism in mice following acute exercise. J Appl Physiol (1985) 118:61-70

Showing the most recent 10 out of 17 publications