<i>BCL11B</i> enhancer hijacking by t(14;16)(q32;q24) translocation defines a novel high-risk subtype of T-ALL
Abstract
Abstract The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cisregulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed-phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2 and activating epithelial-mesenchymal transition transcription signatures. Immunophenotypic and single-cell RNA sequencing analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34+ cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15% to 4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults. Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.
Article Details
Authors (43)
Kaito Mimura
1Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan
Akira Kaino
1Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan
Yotaro Ochi
Yu-Hsuan Chang
4Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Masafumi Seki
June Takeda
1Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan
Saori Katayama
2Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
Hidetaka Niizuma
Yoji Sasahara
Department of Pediatrics, Tohoku University Graduate School of Medicine
Yoko Mizoguchi
7Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan
Maiko Shimomura
7Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan
Ryosuke Koyamada
8Department of Hematology, St. Luke’s International Hospital, Tokyo, Japan
Rintaro Ono
9Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
Daisuke Hasegawa
11Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
Kazuki Mitani
10Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Hirohito Kubota
Satoshi Yoshihara
Nobuhiro Hiramoto
Akihito Otsuki
Yasunobu Okamura
Fumiki Katsuoka
Kengo Kinoshita
Masataka Hasegawa
1Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan
Marina Togo-Ohno
1Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan
Hirona Maeda
3Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Nobuyuki Kakiuchi
Mai Takeuchi
19Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
Aiko Sato-Otsubo
6Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Shota Kato
Kentaro Watanabe
6Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Kotoe Katayama
Seiya Imoto
Yuichi Shiraishi
Katsuyoshi Koh
23Japan Children’s Cancer Group ALL Committee, Nagoya, Japan
Souichi Suenobu
25Japan Association of Childhood Leukemia Study, Kobe, Japan
Eiso Hiyama
27Department of Biomedical Science, Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
Susumu Goyama
4Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Atsuo Kikuchi
Seishi Ogawa
Motohiro Kato
6Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Yasuhito Nannya
Junko Takita
Kenichi Yoshida