Kaito Mimura, Akira Kaino, Yotaro Ochi, Yu-Hsuan Chang, Masafumi Seki, June Takeda, S. Katayama, Hidetaka Niizuma, Yoji Sasahara, Yoko Mizoguchi, Maiko Shimomura, Ryosuke Koyamada, Rintaro Ono, Daisuke Hasegawa, Kazuki Mitani, Hirohito Kubota, Satoshi Yoshihara, Nobuhiro Hiramoto, Akihito Otsuki, Yasunobu Okamura, Fumiki Katsuoka, Kengo Kinoshita, Masataka Hasegawa, Marina Togo-Ohno, Hirona Maeda, Nobuyuki Kakiuchi, Mai Takeuchi, A. Sato-Otsubo, Shota Kato, Kentaro Watanabe, Kotoe Katayama, Seiya Imoto, Yuichi Shiraishi, Katsuyoshi Koh, Souichi Suenobu, Eiso Hiyama, Susumu Goyama, Atsuo Kikuchi, Seishi Ogawa, Motohiro Kato, Y. Nannya, Junko Takita, Kenichi Yoshida
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.