Gut bacterial gene changes following pegaspargase treatment in pediatric patients with acute lymphoblastic leukemia

Abstract

Treatment of pediatric acute lymphoblastic leukemia (ALL) with pegaspargase exploits ALL cells dependency on asparagine. Pegaspargase depletes asparagine, consequentially affecting aspartate, glutamine and glutamate. The gut as a confounding source of these amino acids (AAs) and the role of gut microbiome metabolism of AAs has not been examined. We examined asparagine, aspartate, glutamine and glutamate in stool samples from patients over pegaspargase treatment. Microbial gene-products, which interact with these AAs were identified. Stool asparagine declined significantly, and 31 microbial genes changed over treatment. Changes were complex, and included genes involved in AA metabolism, nutrient sensing, and pathways increased in cancers. While we identified changes in a gene (iaaA) with limited asparaginase activity, it lacked significance after correction leaving open other mechanisms for asparagine decline, possibly including loss from gut to blood. Understanding pathways that change AA availability, including by microbes in the gut, could be useful in optimizing pegaspargase therapy.

Keywords:

• Acute lymphoblastic leukemia
• microbiome
• pegaspargase
• amino acid
• pediatric

Acknowledgements

The authors would like to thank participating children and their families, and the nurses at the IWK Health Centre for assistance with sample collection.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The metagenomic sequencing data used in this study are available under accession numbers PRJEB29237 and PRJEB46214 at the European Nucleotide Archive.

Additional information

Funding

This research was funded by a grant from NSHRF and JD Irving foundation to KK. KAD was funded by an IWK Research Associateship.