BPDCN MYB融合调节细胞周期基因,损害分化并诱发髓系树突状细胞白血病。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-05 DOI:10.1172/jci.insight.183889
Christopher Ag Booth, Juliette M Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A DeCaprio, Andrew A Lane
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引用次数: 0

摘要

MYB 融合经常出现在某些癌症中,包括预后不良的急性白血病--浆细胞性树突状细胞肿瘤(BPDCN)。与其他血癌相比,它们在 BPDCN 中明显富集,而且在某些患者中是唯一检测到的明显体细胞突变。这表明它们本身就足以驱动树突状细胞的转化。据推测,MYB融合会改变MYB的正常转录因子活性,但人们对它们如何促进白血病发生的机理却知之甚少。利用 CUT&RUN 染色质分析,我们发现在 BPDCN 白血病发生过程中,MYB 从树突状细胞系基因的调控因子转变为异常调控 G2/M 细胞周期控制基因。在 BPDCN 患者中发现的 MYB 融合体增加了这些位置 DNA 结合的幅度,这与 BPDCN 相关基因表达的变化有关。此外,MYB融合体在体内的表达会损害树突状细胞的分化并诱导转化,从而产生髓系-树突状急性白血病小鼠模型。在治疗方面,我们提出的证据表明,全反式维甲酸(ATRA)可导致MYB蛋白缺失和BPDCN细胞死亡。
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BPDCN MYB fusions regulate cell cycle genes, impair differentiation and induce myeloid-dendritic cell leukemia.

MYB fusions are recurrently found in select cancers, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared to other blood cancers, and in some patients are the only obvious somatic mutation detected. This suggests they may alone be sufficient to drive dendritic cell transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but mechanistically how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that in BPDCN leukemogenesis, MYB switches from being a regulator of dendritic cell lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in BPDCN patients increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired dendritic cell differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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