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ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression.
Xu, Wenqian; Tian, Feng; Tai, Xiaolu; Song, Gaoxian; Liu, Yuanfang; Fan, Liquan; Weng, Xiangqin; Yang, Eunjeong; Wang, Meng; Bornhäuser, Martin; Zhang, Chao; Lock, Richard B; Wong, Jason W H; Wang, Jin; Jing, Duohui; Mi, Jian-Qing.
Afiliación
  • Xu W; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025.
  • Tian F; Hebei Key Laboratory of Medical Data Science, Institute of Biomedical Informatics, School of Medicine, Hebei University of Engineering, Handan, Hebei Province, 056038.
  • Tai X; Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai.
  • Song G; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025.
  • Liu Y; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025.
  • Fan L; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025.
  • Weng X; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025.
  • Yang E; School of Biomedical Sciences, University of Hong Kong, Hong Kong.
  • Wang M; Songjiang Research Institute, Songjiang District Central Hospital, Institute of Autism and MOE-Shanghai Key Laboratory for Children's Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai. jinwang@shsmu.edu.cn.
  • Bornhäuser M; Medical Clinic I, University Hospital Carl Gustav Carus, TU Dresden, Dresden.
  • Zhang C; Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai.
  • Lock RB; Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine and Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW.
  • Wong JWH; School of Biomedical Sciences, University of Hong Kong, Hong Kong.
  • Wang J; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025.
  • Jing D; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025. jdh12262@rjh.com.cn.
  • Mi JQ; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025. jianqingmi@shsmu.edu.cn.
Haematologica ; 109(8): 2445-2458, 2024 08 01.
Article en En | MEDLINE | ID: mdl-38356460
ABSTRACT
ETV6ACSL6 represents a rare genetic aberration in hematopoietic neoplasms and is often associated with severe eosinophilia, which confers an unfavorable prognosis requiring additional anti-inflammatory treatment. However, since the translocation is unlikely to produce a fusion protein, the mechanism of ETV6ACSL6 action remains unclear. Here, we performed multi-omics analyses of primary leukemia cells and patient-derived xenografts from an acute lymphoblastic leukemia (ALL) patient with ETV6ACSL6 translocation. We identified a super-enhancer located within the ETV6 gene locus, and revealed translocation and activation of the super-enhancer associated with the ETV6ACSL6 fusion. The translocated super-enhancer exhibited intense interactions with genomic regions adjacent to and distal from the breakpoint at chromosomes 5 and 12, including genes coding inflammatory factors such as IL-3. This led to modulations in DNA methylation, histone modifications, and chromatin structures, triggering transcription of inflammatory factors leading to eosinophilia. Furthermore, the bromodomain and extraterminal domain (BET) inhibitor synergized with standard-of-care drugs for ALL, effectively reducing IL-3 expression and inhibiting ETV6ACSL6 ALL growth in vitro and in vivo. Overall, our study revealed for the first time a cis-regulatory mechanism of super-enhancer translocation in ETV6ACSL6ALL, leading to an ALL-accompanying clinical syndrome. These findings may stimulate novel treatment approaches for this challenging ALL subtype.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Translocación Genética / Proteínas de Fusión Oncogénica / Elementos de Facilitación Genéticos / Interleucina-3 / Eosinofilia / Proteínas Proto-Oncogénicas c-ets / Leucemia-Linfoma Linfoblástico de Células Precursoras / Proteína ETS de Variante de Translocación 6 Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Haematologica Año: 2024 Tipo del documento: Article Pais de publicación: Italia
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Translocación Genética / Proteínas de Fusión Oncogénica / Elementos de Facilitación Genéticos / Interleucina-3 / Eosinofilia / Proteínas Proto-Oncogénicas c-ets / Leucemia-Linfoma Linfoblástico de Células Precursoras / Proteína ETS de Variante de Translocación 6 Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Haematologica Año: 2024 Tipo del documento: Article Pais de publicación: Italia