The pharmacogenomics of asparaginase‐mediated toxicities in acute lymphoblastic leukemia (ALL) patients

Abstract

The bacterial enzyme L‐asparaginase (ASNase) is an essential component of effective combination chemotherapy for the treatment of acute lymphoblastic leukemia (ALL). However, the development of immune‐mediated toxicities to this agent can increase the risk of leukemia relapse in children, whereas the high risk of liver injury limits the use of ASNase in adults despite its benefit on treatment outcome. The overarching goal of our studies is to understand the underlying molecular mechanisms of common asparaginase‐mediated toxicities that lead to poor treatment outcome by integrating genome‐wide association studies (GWAS) and experimental validations using genetic and pharmacological models.In the first example, we focused on ASNase‐induced immunotoxicity. We identified by GWAS a higher risk of ASNase immunotoxicity among carriers of the nuclear factor of activated T‐cells, cytoplasmic, calcineurin‐dependent 2 (NFATC2) rs6021191 variant, which leads to elevated expression of this transcription factor involved in the regulation of immune responses. Consistent with our GWAS results, we found the NFATc2‐deficient mice were protected from ASNase‐induced immunotoxicity. Furthermore, we have demonstrated that the pharmacological inhibition of the NFAT pathway in wild‐type mice yields similar protection as NFATc2 deficiency. Current research aims to develop a selective inhibitor of calcineurin‐mediated NFATc2 activation that is expected to attenuate ASNase‐induced immunotoxicity in pediatric ALL patients.In another example, we focused on ASNase‐induced hepatotoxicity, including steatosis. Our group led the first GWAS of ASNase hepatotoxicity and identified an association between the patatin‐like phospholipase domain‐containing 3 (PNPLA3) I148M variant and alanine aminotransferase (ALT) levels after ASNase therapy. The PNPLA3 I148M variant is associated with the development of non‐alcoholic liver disease (NAFLD) and our results are the first to link the variant to drug‐induced liver injury. Consistent with our GWAS, mice treated with ASNase develop fatty livers after a single dose. Additional studies elucidating the mechanism of the toxicity have identified a novel mechanism of drug‐induced liver injury involving ASNase‐induced adipose tissue lipolysis, systemic free fatty acid mobilization, hepatic triglyceride accumulation, and fatty acid‐induced liver injury. Our lab has further demonstrated that pharmacological inhibition of adipose triglyceride lipase (Atgl), which is a key enzyme involved in adipose lipolysis, protects from ASNase‐mediated liver injury. We believe inhibition of ASNase‐induced steatosis will help expand ASNase therapy to adult ALL patients.In summary, our studies are clinically relevant and highly translational. Our ultimate goal is to improve ALL survival by mitigating ASNase‐induced toxicities and ensuring that patients can benefit from the therapeutic effect of ASNase on leukemias.Support or Funding InformationThis study was supported by the University of Pittsburgh School of Pharmacy and the NIH Grant RO1 CA216815.