Mentor Name: Mignon Loh

Our overarching goal is to systematically uncover the genomic heterogeneity of pediatric and adolescent/young adult (AYA) Philadelphia chromosome-positive (Ph+) and ABL-class Ph-like acute lymphoblastic leukemia (ALL) to identify 1) genetic predictors of relapse and 2) therapeutic vulnerabilities. While the long-term survival rate of childhood ALL exceeds 90% with contemporary chemotherapy, the outcome of pediatric and AYA patients with BCR::ABL1-driven acute leukemia remains poor, even with the addition of tyrosine kinase inhibitors. Since 2012, a myriad of ABL-class fusions involving ABL1, ABL2, CSF1R, KIT, LYN, PDGFRA and PDGFRB was discovered. Patients with ABL-class Ph-like ALL also have poor outcomes, with 5-year event free survival (EFS) <60%. Our central hypothesis is that genetic alterations mediating therapeutic resistance leading to clinical relapse can be identified via a comprehensive multi-omics profiling of a large cohort of patients uniformly treated on a clinical trial, and these resistance drivers will harbor novel therapeutic targets. We will leverage the unique resource of patient samples and clinical data collected on Children’s Oncology Group (COG) AALL1631, the largest prospective international study for pediatric/AYA Ph+ and ABL-class Ph-like ALL to date. Using comprehensive genomic data (funded from other sources, including a supplemental BIQSFP award) generated from paired diagnostic/germline samples collected from patients enrolled on AALL1631, we will first identify predictors of relapse in Ph+ and ABL-class Ph-like ALL and further determine the therapeutic value of major secondary events via cell proliferation and pharmacologic inhibitor screens in engineered cell line models of Ph+ and ABL-class Ph-like ALL harboring these secondary events. We will test the efficacy of the most compelling candidate compounds in patient-derived xenograft (PDX) models established from samples collected on AALL1631.