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
  • 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. [email protected].
  • 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. [email protected].
  • 17. Department of Vascular Medicine, National Reference Center of Rare Lymphatic and Vascular Diseases, UA11 INSERM - UM IDESP, Campus Santé, Montpellier Cedex 5, France. [email protected].
  • 18. Division of Paediatric Hematology and Oncology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. [email protected].
  • # 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.
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