The ETV6-ABL1 fusion is a rare genetic aberration classified as Philadelphia chromosome-like high-risk B-cell precursor acute lymphoblastic leukemia. We present the case of a child with multiply relapsed B-cell precursor acute lymphoblastic leukemia in which next-generation sequencing identified this cryptic fusion, undetected by standard testing, resulting in sustained clinical response to targetted therapy with imatinib. Upon subsequent relapse, repeat next-generation sequencing identified an additional aberration, MLL2-ADCY9, as a possible molecular driver conferring resistance to therapy. This report demonstrates the exciting potential of integrative clinical sequencing in identifying previously undetected actionable findings leading to improved outcomes in pediatric oncology patients.