modeling of TKI resistance in the high-risk B-cell acute lymphoblastic leukemia fusion gene - implications for targeted therapy.

Acute lymphoblastic leukemia remains a leading cause of cancer-related death in children. Furthermore, subtypes such as Ph-like ALL remain at high-risk of relapse, and treatment resistance remains a significant clinical issue. The patient-derived Ph-like ALL fusion gene was transduced into Ba/F3 cells and allowed to become resistant to the tyrosine kinase inhibitors (TKIs) imatinib or dasatinib, followed by secondary resistance to ponatinib. Ba/F3 cells developed the clinically relevant p.T315I mutation and upon secondary resistance to ponatinib, developed compound mutations, including a novel p.L302H mutation. Significantly, compound mutations were targetable with a combination of asciminib and ponatinib. modeling of Ph-like ALL has identified kinase domain mutations in response to TKI treatment, that may have important clinical ramifications. Early detection of mutations is paramount to guide treatment strategies and improve survival in this high-risk group of patients.