دورية أكاديمية
ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression
| العنوان: | ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression |
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| المؤلفون: | 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 |
| المصدر: | Haematologica, Vol 999, Iss 1 (2024) |
| بيانات النشر: | Ferrata Storti Foundation, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Diseases of the blood and blood-forming organs |
| مصطلحات موضوعية: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 0390-6078 1592-8721 |
| العلاقة: | https://haematologica.org/article/view/11446Test; https://doaj.org/toc/0390-6078Test; https://doaj.org/toc/1592-8721Test |
| DOI: | 10.3324/haematol.2023.284121 |
| الوصول الحر: | https://doaj.org/article/907b7a1e73c4467b8401e93a54a64c67Test |
| رقم الانضمام: | edsdoj.907b7a1e73c4467b8401e93a54a64c67 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 03906078 15928721 |
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| DOI: | 10.3324/haematol.2023.284121 |