<i>ETV6::ACSL6</i> translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression
Wenqian Xu,
Feng Tian,
Xiaolu Tai,
Gaoxian Song,
Yuanfang Liu,
Liquan Fan,
Xiangqin Weng,
Eunjeong Yang,
Meng Wang,
Martin Bornhäuser,
Chao Zhang,
Richard B. Lock,
Jason W.H. Wong,
Jin Wang,
Duohui Jing,
Jian-Qing Mi
Affiliations
Wenqian Xu
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
Feng Tian
Hebei Key Laboratory of Medical Data Science, Institute of Biomedical Informatics, School of Medicine, Hebei University of Engineering, Handan, Hebei Province, 056038
Xiaolu Tai
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai
Gaoxian Song
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
Yuanfang Liu
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
Liquan Fan
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
Xiangqin Weng
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
Eunjeong Yang
School of Biomedical Sciences, University of Hong Kong, Hong Kong
Meng Wang
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
Martin Bornhäuser
Medical Clinic I, University Hospital Carl Gustav Carus, TU Dresden, Dresden
Chao Zhang
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai
Richard B. Lock
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
Jason W.H. Wong
School of Biomedical Sciences, University of Hong Kong, Hong Kong
Jin Wang
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
Duohui Jing
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
Jian-Qing Mi
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
ETV6::ACSL6 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 ETV6::ACSL6 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 ETV6::ACSL6 translocation. We identified a super-enhancer located within the ETV6 gene locus and revealed translocation and activation of the super-enhancer associated with the ETV6::ACSL6 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 ETV6::ACSL6 ALL growth in vitro and in vivo. Overall, our study revealed for the first time a cis-regulatory mechanism of super-enhancer translocation in ETV6::ACSL6 ALL, leading to ALL-accompanying clinical syndrome. These findings may stimulate novel treatment approaches for this challenging ALL subtype.
