Self-reinforcing IL-1β signaling accelerates the development and recurrence of <i>TCF3</i> :: <i>HLF</i> -positive B-ALL
Abstract
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.
Article Details
Authors (19)
Aisa Suzuki
1Division of Immunology and Allergy, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
Tsukasa Shigehiro
1Division of Immunology and Allergy, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
Mayumi Hirakawa
1Division of Immunology and Allergy, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
Risa Hirano
1Division of Immunology and Allergy, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
Minori Tamai
2Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
Koshi Akahane
2Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
Kazuo Okamoto
Kanazawa University, Kanazawa, Japan
Hiroshi Takayanagi
Yuya Terashima
5Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Shinjuku, Japan
Satoshi Ueha
Division of Molecular Regulation of Inflammatory and Immune Diseases, Tokyo University of Science
Toshimori Kitami
6Laboratory for Metabolic Networks, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Masatoshi Takagi
Dai Keino
8Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan
Keisuke Kato
9Division of Pediatric Hematology/Oncology, Ibaraki Prefectural Children’s Hospital, Ibaraki, Japan
Hiroshi Kawaguchi
10Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Moeko Hino
11Department of Pediatrics, School of Medicine, Chiba University, Chiba, Japan
Akihiko Yoshimura
Takeshi Inukai
Tomokatsu Ikawa
1Division of Immunology and Allergy, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan