Self-reinforcing IL-1β signaling accelerates the development and recurrence of TCF3 :: HLF -positive B-ALL

ABSTRACT: The TCF3::HLF fusion protein defines a highly aggressive and incurable subtype of B-cell acute lymphoblastic leukemia (B-ALL). Using a newly established mouse model that faithfully recapitulates human TCF3::HLF B-ALL, including osteolytic bone lesions, we identified self-reinforcing interleukin-1β (IL-1β) signaling networks as a central driver of disease progression. TCF3::HLF B-ALL cells displayed marked upregulation of inflammatory cytokines, such as IL1B, IL6, and IFNG. Genetic deletion of IL1B or its receptor IL1R1 suppressed leukemic growth, reduced expression of receptor activator of nuclear factor κB ligand, and ameliorated bone destruction in vivo. Epigenetic profiling revealed a previously unrecognized intronic regulatory element within the IL1B locus bound directly by TCF3::HLF. Importantly, single-cell RNA sequencing of patient samples demonstrated strong IL1B induction at relapse compared with diagnosis, underscoring its clinical relevance. Collectively, these findings establish the TCF3::HLF-IL-1β axis as a critical determinant of leukemic propagation and bone pathology and highlight IL-1β blockade as a potential therapeutic strategy for this otherwise incurable leukemia.