TY - JOUR
T1 - KRAS-driven model of Gorham-Stout disease effectively treated with trametinib
AU - Homayun-Sepehr, Nassim
AU - McCarter, Anna L.
AU - Helaers, Raphaël
AU - Galant, Christine
AU - Boon, Laurence M.
AU - Brouillard, Pascal
AU - Vikkula, Miikka
AU - Dellinger, Michael T.
N1 - Funding Information:
Three of the authors (CG, LMB, and MV) of this publication are members of the Vascular Anomalies Working Group (VASCA WG) of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN) (project ID: 769036). We are grateful to the patient for the invaluable participation. The authors would like to thank Dave Primm of the UT Southwestern Department of Surgery for help in editing this article. These studies were supported by a grant from the NIH (1R01HL144793-01 to MTD) and by grants from the Fonds de la Recherche Scientifique (FNRS) (T.0026.14 and T.0247.19 to MV and T.0146.16 to LMB), the Fund Generet managed by the King Baudouin Foundation (to MV), and by la Région wallonne dans le cadre du financement de l'axe stratégique FRFS-Walloon Excellence in Life Sciences and Biotechnology (to MV). These studies were also funded by the Lymphatic Malformation Institute USA (to MV). NHS is a doctoral student supported by a fellowship from Télévie, and PB is a Scientific Logistics Manager of the Genomics Platform of University of Louvain. We also thank the National Lottery, Belgium, and the Foundation against Cancer (2010-101), Belgium, for their support to the Genomics Platform of University of Louvain and de Duve Institute as well as FNRS for equipment grant U.N035.17 for the “Big data analysis cluster for NGS at UCLouvain.”
Funding Information:
Three of the authors (CG, LMB, and MV) of this publication are members of the Vascular Anomalies Working Group (VASCA WG) of the European Reference Network for Rare Multisystemic Vascular Diseases (VAS-CERN) (project ID: 769036). We are grateful to the patient for the invaluable participation. The authors would like to thank Dave Primm of the UT Southwestern Department of Surgery for help in editing this article. These studies were supported by a grant from the NIH (1R01HL144793-01 to MTD) and by grants from the Fonds de la Recherche Scientifique (FNRS) (T.0026.14 and T.0247.19 to MV and T.0146.16 to LMB), the Fund Generet managed by the King Baudouin Foundation (to MV), and by la Région wallonne dans le cadre du financement de l’axe stratégique FRFS-Walloon Excellence in Life Sciences and Biotechnology (to MV). These studies were also funded by the Lymphatic Malformation Institute USA (to MV). NHS is a doctoral student supported by a fellowship from Télévie, and PB is a Scientific Logistics Manager of the Genomics Platform of University of Louvain. We also thank the National Lottery, Belgium, and the Foundation against Cancer (2010-101), Belgium, for their support to the Genomics Platform of University of Louvain and de Duve Institute as well as FNRS for equipment grant U.N035.17 for the “Big data analysis cluster for NGS at UCLouvain.” Address correspondence to: Michael Dellinger, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, USA. Phone: 214.648.4907; Email: michael.dellinger@utsouthwestern.edu. Or to: Miikka Vikkula, de Duve Institute, University of Louvain, Avenue Hippocrate 74 (+5), bte B1.74.06, B-1200 Brussels, Belgium. Phone: 32.2.764.7490; Email: miikka.vikkula@uclouvain.be.
Publisher Copyright:
Copyright: © 2021, Homayun-Sepehr et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/8/9
Y1 - 2021/8/9
N2 - Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.
AB - Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.
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U2 - 10.1172/jci.insight.149831
DO - 10.1172/jci.insight.149831
M3 - Article
C2 - 34156985
AN - SCOPUS:85112272400
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - e149831
ER -