GSE122243
The hepatic integrated stress response to asparaginase corresponds with transcriptional signatures that differ with age.
Clinical reports describing increased liver toxicity in adult versus pediatric patients treated with the anti-leukemic drug asparaginase suggest that hepatic stress responses differ with age. We utilized RNA sequencing to comparatively examine the liver transcriptomes of juvenile (2 wk old) and adult (8 and 16 wk old) mice following chronic exposure to asparaginase.  Liver RNA from 2 and 16 week old mice were sent Sulzberger Columbia Genome Center for cDNA library preparation and sequencing at the same time as liver RNA from 8 week old mice (GSE92364). Asparaginase exposure altered the liver transcriptomes only modestly whereas age had a massive global influence. Unbiased exploration into the effect of age on drug responses revealed that the integrated stress response (ISR) represented a common, core molecular signature regardless of age. ISR engagement in juveniles corresponded with transcriptional signatures of downregulated lipid biosynthesis and increased sequestration of iron. In contrast, adults showed ISR activation alongside upregulation of Saa1 and Saa2 inflammatory markers, serine/glycine metabolism, and folate cycle suggesting mitochondrial stress. We also observed sporadic enrichment in RNA gene signatures reflecting altered nucleotide metabolism of adults in response to the drug. Taken together, our data show that maturity to adulthood does not alter the ISR gene signature to asparaginase. Instead, age-related changes in cellular resource capacity and turnover may be the determining factor in guiding hepatic stress responses to asparaginase. Overall design: RNA-seq analysis of livers of 2, 8, and 16 wk old mice that were exposed chronically to asparaginase (3 international units per gram body weight daily over 7 days for 2- and 16- wk old mice and over 8 days for 8 wk old mice) or equivolume excipient (phosphate buffered saline).  All mice were on the C57BL/6J genetic background for at least 8 generations. Three mice were used for each genotype and treatment (Total = 18 samples).