Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition.
Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition.
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DOI：
10.1172/jci.insight.155888
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发表时间：
2023-05-08
期刊：
影响因子：
8
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
--
作者：
Sheppard, Sarah E.;March, Michael E.;Seiler, Christoph;Matsuoka, Leticia S.;Kim, Sophia E.;Kao, Charlly;Rubin, Adam I.;Battig, Mark R.;Khalek, Nahla;Schindewolf, Erica;O'Connor, Nora;Pinto, Erin;Priestley, Jessica R. C.;Sanders, Victoria R.;Niazi, Rojeen;Ganguly, Arupa;Hou, Cuiping;Slater, Diana;Frieden, Ilona J.;Huynh, Thy;Shieh, Joseph T.;Krantz, Ian D.;Guerrero, Jessenia C.;Surrey, Lea F.;Biko, David M.;Laje, Pablo;Castelo-Soccio, Leslie;Nakano, Taizo A.;Snyder, Kristen;Smith, Christopher L.;Li, Dong;Dori, Yoav;Hakonarson, Hakon
中枢传导淋巴管异常（CCLA）由于先天性发育不良的神经系统，可导致衰弱和危及生命的疾病，治疗选择有限。我们确定了4个人与CCLA，水肿，微囊淋巴管畸形由于致病性，镶嵌变异KRAS。为了确定这些变体的功能影响并确定针对这些个体的靶向治疗，我们使用原代人真皮淋巴管内皮细胞（HDLEC）和斑马鱼幼虫来模拟淋巴管发育不良。p.Gly12Asp和p.Gly13Asp变体在2维（2D）模型和3D类器官模型中的HDLEC中的表达导致ERK磷酸化增加，证明这些变体激活RAS/MAPK通路。斑马鱼静脉和淋巴管内皮中激活KRAS变体的表达导致淋巴发育不良和水肿，与研究中的个体相似。用MEK抑制剂处理显著降低了类器官和斑马鱼模型系统中的表型。总之，我们提出了所观察到的淋巴异常的分子特征，由于致病性，体细胞，激活KRAS变体在人类。我们的临床前研究表明，由于激活KRAS致病性变体，应在未来的CCLA临床试验中研究MEK抑制。
Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.
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