2. Academic Validation
  3. Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition

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

  • Angiogenesis. 2024 Jul 5. doi: 10.1007/s10456-024-09934-8.
Friedrich G Kapp # 1,  Farhad Bazgir # 2,  Nagi Mahammadzade # 3,  Mehrnaz Mehrabipour 2,  Erik Vassella 4,  Sarah M Bernhard 5 6,  Yvonne Döring 5 6 7,  Annegret Holm 3 8,  Axel Karow 9,  Caroline Seebauer 10,  Natascha Platz Batista da Silva 11,  Walter A Wohlgemuth 12,  Aviv Oppenheimer 3,  Pia Kröning 13,  Charlotte M Niemeyer 3,  Denny Schanze 14,  Martin Zenker 14,  Whitney Eng 15,  Mohammad R Ahmadian 2,  Iris Baumgartner 5 6,  Jochen Rössler 16 17 18
Affiliations

Affiliations

  • 1 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, VASCERN VASCA European Reference Centre, 79106, Freiburg, Germany. friedrich.kapp@uniklinik-freiburg.de.
  • 2 Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
  • 3 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, VASCERN VASCA European Reference Centre, 79106, Freiburg, Germany.
  • 4 Institute of Pathology and Tissue Medicine, University of Bern, Bern, Switzerland.
  • 5 Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, Bern, Switzerland.
  • 6 Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
  • 7 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University Munich, Pettenkoferstr 9, 80336, Munich, Germany.
  • 8 Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
  • 10 Department of Otorhinolaryngology, Regensburg University Medical Center, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
  • 11 Department of Radiology, Regensburg University Medical Center, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
  • 12 University Clinic and Policlinic of Radiology at the Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
  • 13 Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany.
  • 14 Institute of Human Genetics, University Hospital Magdeburg, 39120, Magdeburg, Germany.
  • 15 Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • 16 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, VASCERN VASCA European Reference Centre, 79106, Freiburg, Germany. jochen.roessler@insel.ch.
  • 17 Department of Vascular Medicine, National Reference Center of Rare Lymphatic and Vascular Diseases, UA11 INSERM - UM IDESP, Campus Santé, Montpellier Cedex 5, France. jochen.roessler@insel.ch.
  • 18 Division of Paediatric Hematology and Oncology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. jochen.roessler@insel.ch.
  • # Contributed equally.
PMID: 38969873 DOI: 10.1007/s10456-024-09934-8
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.

Keywords

Arteriovenous malformation; RAS-MAPK pathway; RIT1; Trametinib; Vascular anomalies; Vascular malformation.

Figures
Products