Ernesto Diaz-Flores, PhD

Acute lymphoblastic leukemia is the leading cause of cancer mortality in children and young adults. Notably, almost 10% of children and adolescents cancer patients present germline predisposition mutations. Li-Fraumeni Syndrome (germline mutations in TP53), was reported the most common cancer predisposition syndrome in the Pediatric Cancer Genome Project. Low hypodiploid B-cell lymphoblastic leukemia (LH B-ALL), an aggressive leukemia characterized by mutations in TP53 in more than 90% of patients, of which nearly 50% represent Li-Fraumeni syndrome results in 70% mortality compared to 15% for B-ALL patients overall. Aiming to turn this aggressive disease into one with a much-improved prognosis, we investigated therapeutic targets specific to hypodiploid leukemia with p53 mutations. Importantly, TP53, the most commonly mutated gene in cancer is especially prevalent at relapse after aggressive therapies. We exposed LH-B-ALL patient samples to APR-246, a drug targeting the p53, already in use in late phase clinical trials. These studies revealed complete induction of cell death in LH-B-ALL by APR-246. Moreover, gene expression analyses indicated that cells expressing mutant TP53 present overexpressed surface proteins. I hypothesize that hypodiploid leukemia with mutant TP53 can be selectively identified and targeted. I, thus, propose two therapeutic opportunities (pharmacological and immunotherapy) to reverse the dim prognosis for patients with LH-B-ALL harboring p53 mutations.