CADASIL NOTCH3 突变导致克隆造血和 Dnmt3a-R878H 造血克隆的扩增

IF 12.8 1区 医学 Q1 HEMATOLOGY
Raúl Sánchez-Lanzas, Justin Barclay, Alexandros Hardas, Foteini Kalampalika, Amanda Jiménez-Pompa, Paolo Gallipoli, Miguel Ganuza
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引用次数: 0

摘要

克隆造血(CH)在老年人中几乎普遍存在。人们对驱动克隆性造血的分子和细胞机制以及携带克隆性突变成熟血细胞的临床后果知之甚少。我们最近发现,NOTCH3 细胞外结构域(ECD)中的 C223Y 突变是小鼠 CH 的潜在驱动因素。具有讽刺意味的是,扰乱半胱氨酸数量的种系NOTCH3 ECD突变会导致大脑常染色体显性动脉病伴有皮质下梗塞和白质脑病(CADASIL),这是一种血管性痴呆,这表明CADASIL和CH之间存在意想不到的联系。在这里,我们正式证明了表达与CADASIL相关的NOTCH3C455R的小鼠造血干细胞和祖细胞(HSPCs)具有增殖优势,能在体内和体外实现强大的细胞扩增。NOTCH3C455R和Dnmt3aR878H(与一种常见的人类CH突变同源)的共同表达提高了NOTCH3C455R HSPC的适应性,证明了它们之间的功能合作。令人惊讶的是,NOTCH3C455R 造血细胞的存在支持了 Dnmt3aR878H HSPCs 在体内的非细胞自主扩增,这有力地表明 CADASIL 患者和无症状携带者极易发生 DNMT3AR882H 驱动的 CH。考虑到CADASIL相关的NOTCH3突变在普通人群中的发生率高于预期(约每400人中就有1名携带者),因此应考虑这些NOTCH3突变对CH发展的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones

A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones

Clonal hematopoiesis (CH) is nearly universal in the elderly. The molecular and cellular mechanisms driving CH and the clinical consequences of carrying clonally derived mutant mature blood cells are poorly understood. We recently identified a C223Y mutation in the extracellular domain (ECD) of NOTCH3 as a putative CH driver in mice. Provocatively, germline NOTCH3 ECD mutations perturbing cysteine numbers cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a type of vascular dementia, suggesting an unexpected link between CADASIL and CH. Here, we formally demonstrated that mouse hematopoietic stem and progenitor cells (HSPCs) expressing CADASIL-related NOTCH3C455R exhibit a proliferative advantage resulting in robust cellular expansion in vivo and in vitro. Co-expression of NOTCH3C455R and Dnmt3aR878H, homologous to a frequent human CH mutation, increased the fitness of NOTCH3C455R HSPCs, demonstrating their functional cooperation. Surprisingly, the presence of NOTCH3C455R hematopoietic cells supported the expansion of Dnmt3aR878H HSPCs in a non-cell autonomous fashion in vivo, strongly suggesting that CADASIL patients and asymptomatic carriers can be highly predisposed to DNMT3AR882H-driven CH. Considering that CADASIL-related NOTCH3 mutations are more frequent in the general population than anticipated (~1 carrier in 400 people), the effect of these NOTCH3 mutations on CH development should be considered.

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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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