Senior Vice Chancellor's Research Seminar

Topic Overview:

L-asparaginase (ASNase) is essential in the treatment of acute lymphoblastic leukemia (ALL). However, the development of immune-mediated toxicities to this agent can increase the risk of relapse in children, whereas the high risk of liver injury limits the use of ASNase in adults. The overarching goal of Fernandez’s studies is to understand the underlying mechanisms of ASNase-mediated toxicities that lead to poor treatment outcomes by integrating genome-wide association studies (GWAS) and experimental validations using genetic and pharmacological models.

Regarding ASNase-induced immunotoxicity, Fernandez and colleagues used GWAS to identify a higher risk of ASNase immunotoxicity among carriers of the nuclear factor of activated T cells, cytoplasmic 2 (NFATC2) rs6021191 variant, which leads to elevated expression of this transcription factor involved in the regulation of immune responses. Consistent with their GWAS, NFATC2-deficient mice are protected from ASNase-induced immunotoxicity due to attenuated IL-4 responses that lead to decreased Th2 cytokine levels, lower IgE and antigen-specific antibody levels, and decreased FcεR1 expression.

Fernandez and colleagues’ clinical studies involving ASNase-induced liver injury identified by GWAS an association between the patatin-like phospholipase domain-containing 3 (PNPLA3) I148M variant and alanine aminotransferase (ALT) levels. The PNPLA3 I148M variant is associated with the development of nonalcoholic fatty liver disease (NAFLD) and, consistent with their GWAS, mice treated with ASNase develop fatty livers. Additional studies have elucidated a novel mechanism of liver injury involving ASNase-induced adipose tissue lipolysis, systemic free fatty acid mobilization, and fatty acid-induced liver injury.

Fernandez and colleagues’ ultimate goal is to improve ALL survival by mitigating ASNase-induced toxicities and ensuring therapeutic drug exposures.















	View on Pitt Calendar Topic Overview: L-asparaginase (ASNase) is essential in the treatment of acute lymphoblastic leukemia (ALL). However, the development of immune-mediated toxicities to this agent can increase the risk of relapse in children, whereas the high risk of liver injury limits the use of ASNase in adults. The overarching goal of Fernandez’s studies is to understand the underlying mechanisms of ASNase-mediated toxicities that lead to poor treatment outcomes by integrating genome-wide association studies (GWAS) and experimental validations using genetic and pharmacological models. Regarding ASNase-induced immunotoxicity, Fernandez and colleagues used GWAS to identify a higher risk of ASNase immunotoxicity among carriers of the nuclear factor of activated T cells, cytoplasmic 2 (NFATC2) rs6021191 variant, which leads to elevated expression of this transcription factor involved in the regulation of immune responses. Consistent with their GWAS, NFATC2-deficient mice are protected from ASNase-induced immunotoxicity due to attenuated IL-4 responses that lead to decreased Th2 cytokine levels, lower IgE and antigen-specific antibody levels, and decreased FcεR1 expression. Fernandez and colleagues’ clinical studies involving ASNase-induced liver injury identified by GWAS an association between the patatin-like phospholipase domain-containing 3 (PNPLA3) I148M variant and alanine aminotransferase (ALT) levels. The PNPLA3 I148M variant is associated with the development of nonalcoholic fatty liver disease (NAFLD) and, consistent with their GWAS, mice treated with ASNase develop fatty livers. Additional studies have elucidated a novel mechanism of liver injury involving ASNase-induced adipose tissue lipolysis, systemic free fatty acid mobilization, and fatty acid-induced liver injury. Fernandez and colleagues’ ultimate goal is to improve ALL survival by mitigating ASNase-induced toxicities and ensuring therapeutic drug exposures.
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