涉及增强子劫持的结构变异会诱导异常癌基因表达并导致肿瘤发生。一种罕见的易位 t(3;8)(q26.2;q24) 与 MECOM 和 MYC 重排相关，导致骨髓肿瘤预后不佳。世界卫生组织最新分类将 MECOM 重排的髓系肿瘤视为具有遗传异常的急性髓系白血病 (AML)。最近，诱导多能干细胞（iPSC）技术的越来越多的使用有助于阐明血液恶性肿瘤的致病过程。然而，其在研究髓系肿瘤中增强子劫持的效用仍不清楚。在本研究中，我们从携带 t(3;8)(q26.2;q24) 的骨髓增生异常综合征 (MDS) 患者中生成 iPSC 系，并将其分化为造血祖细胞，以用 t(3;8) 模拟 MDS 的病理生理学（q26.2；q24）。我们的 iPSC 模型再现了原发患者的 MECOM 表达变化以及 MECOM 启动子和 MYC 血液增强子簇 (BENC) 中的组蛋白 H3 赖氨酸 27 乙酰化 (H3K27ac) 模式。此外，我们揭示了溴结构域和额外末端基序 (BET) 抑制剂通过抑制活化的 MECOM 对 iPSC 衍生的 MDS 细胞的凋亡作用。我们的研究证明了 iPSC 模型对于揭示染色体结构变化导致的增强子劫持的精确机制以及发现癌症治疗的潜在候选治疗药物的有用性。© 2024 作者。英国血液学杂志由英国血液学会和约翰·威利出版

Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.