IRF2BP2::JAK2 Defines a Novel Kinase-Activating Fusion in Pediatric T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous and clinically aggressive malignancy, where outcomes remain poor for patients with early relapse or refractory disease. Although tyrosine kinase alterations represent potentially actionable lesions, understanding of their functional and therapeutic relevance in T-ALL is limited. Here, we report the first case of an IRF2BP2::JAK2 fusion in a pediatric patient with high-risk T-ALL, identified through whole-genome and transcriptome sequencing. Using CRISPR-Cas9 genome engineering, we modeled the Irf2bp2::Jak2 fusion in Ba/F3 cells and showed that it confers cytokine-independent growth, localizes to the cytoplasm, and drives constitutive JAK-STAT signaling. Importantly, both type I (ruxolitinib) and type II (CHZ868) JAK inhibitors potently inhibited the fusion. These findings establish IRF2BP2::JAK2 as a novel oncogenic driver and druggable vulnerability in T-ALL and represent the first reported instance of an IRF2BP2 fusion directly activating a non-receptor tyrosine kinase. More broadly, this work underscores the critical role of functional modeling in defining the biological and therapeutic significance of rare genomic alterations to enable the translation of precision medicine to the clinic.