Mitochondrial Dysfunction underlies treatment related hepatotoxicity in Hispanics with acute lymphoblastic leukemia

PROJECT TITLE: Mitochondrial dysfunction underlies treatment related hepatotoxicity in Hispanics with
acute lymphoblastic leukemia
ABSTRACT:
Acute Lymphoblastic leukemia is the most common type of cancer in children with higher prevalence in
Hispanics. While overall survival for children with acute lymphoblastic leukemia (ALL) has reached approximately
90%, the outcome for adult patients with ALL remains poor (<45%). Hispanic children and adolescent and young
adult (AYA) both also suffer inferior outcomes. The intensive use of asparaginase in pediatric regimens has
enhanced the cure rate of children, but the higher rate of asparaginase-related toxicity in adults has limited its
widespread use in this age group. Hepatotoxicity is a particularly important drug-induced contraindication, as
current recommendations of withholding asparaginase treatment when grade 3 or 4 hepatotoxicity develops,
which occurs in approximately 30% of ALL patients, may compromise its therapeutic effect. Hispanic patients
developed hepatotoxicity at an increased rate compared with other ethnicities. Obese and/or older children are
particularly at risk for hepatotoxicity. Unfortunately, pharmacogenomic studies of asparaginase in ALL are limited
and mostly focus on Caucasian pediatric patients. In a predominantly non-Hispanic population, we previously
reported that genetic variant rs4880 in SOD2, which encodes a key mitochondrial enzyme protective against
reactive oxygen species (ROS), is associated with asparaginase-induced hepatotoxicity in adult ALL patients.
The high-risk CC genotype is more common in Hispanic individuals, who also exhibit a greater prevalence of
ALL and asparaginase-induced hepatotoxicity than other ethnicities. In a largely Hispanics cohort of 143 pediatric
patients with ALL who have received asparaginase based regimen, we found higher elevation of liver enzymes
post treatment with asparaginase in Hispanics than non-Hispanics. The rs4880 CC genotype was significantly
also more frequent in Hispanics and was associated with elevated liver enzymes post asparaginase treatment
and higher body mass index which was also higher is Hispanic patients. Altogether, these data suggest an
oxidative stress etiology involved in a wide range of metabolic disorders leading to liver toxicities associated with
asparaginase in patients with ALL. Here we propose to explore the link between the mitochondrial enzymes and
mitochondrial dysfunction and asparaginase induced hepatotoxicity in Hispanics. We hypothesize that
mitochondrial dysfunction and oxidative stress contribute to asparaginase-induced hepatotoxicity in
Hispanics. Our aims are: Aim 1) Identify genetic and metabolic alterations in the mitochondria that contribute
to asparaginase-induced hepatotoxicity in Hispanics. Aim 2) Develop a computational model to predict
asparaginase-induced hepatotoxicity in Hispanic patients with ALL.
Our study will provide functional evidence of the association between the mitochondrial dysfunction and
asparaginase related hepatotoxicity in Hispanics and provide clinically useful tool for predicting asparaginase-
induced hepatotoxicity in Hispanic patients with ALL. More broadly, our findings will reveal mechanistic insights
needed to develop therapies with reduced toxicity and improved efficacy in patients with ALL.

Grant Number: 1R21CA274416-01A1
NIH Institute/Center: NIH
Principal Investigator: Houda Alachkar