Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Angiogenesis Pub Date : 2024-07-05 DOI:10.1007/s10456-024-09934-8
Friedrich G. Kapp, Farhad Bazgir, Nagi Mahammadzade, Mehrnaz Mehrabipour, Erik Vassella, Sarah M. Bernhard, Yvonne Döring, Annegret Holm, Axel Karow, Caroline Seebauer, Natascha Platz Batista da Silva, Walter A. Wohlgemuth, Aviv Oppenheimer, Pia Kröning, Charlotte M. Niemeyer, Denny Schanze, Martin Zenker, Whitney Eng, Mohammad R. Ahmadian, Iris Baumgartner, Jochen Rössler
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Abstract

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

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动静脉畸形中的体细胞 RIT1 delins 可使 RAS-MAPK 信号超活化,从而适用于 MEK 抑制。
动静脉畸形(AVM)是一种良性血管畸形,容易引起疼痛、出血和进行性生长。动静脉畸形主要是由 RAS-MAPK 通路的镶嵌致病变体引起的。然而,并非所有患者都能找到致病变体。通过超深度测序,我们在三名 AVM 患者的病变组织中发现了新型体细胞 RIT1 delins 变异。RIT1 编码一种 RAS 样蛋白,可调节 RAS-MAPK 信号转导。我们在 HEK293T 细胞中表达了 RIT1 变体,这导致 ERK1/2 磷酸化强烈增加。在斑马鱼胚胎中,内皮特异性镶嵌式过表达 RIT1 delins 会诱导 AVM 的形成,这突显了它们在血管发育中的重要功能。体外的 ERK1/2 过度激活和体内的 AVM 形成均可被药物 MEK 抑制所抑制。使用MEK抑制剂曲美替尼治疗后,一名患者的出血发作和AVM大小明显减少。我们的研究结果表明 RIT1 与 AVM 的形成有关,并为靶向治疗的临床试验提供了依据。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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