Targeting KIT prevents brain arteriovenous malformations driven by ALK1-deficient angiogenic endothelial cells.

Loss of ACVRL1/ALK1 signalling relieves BMP9-ALK1-SMAD4 repression of KIT and drives emergence of a KIT+ angiogenic endothelial population with tip-cell signature and activation of PI3K and KRAS pathways.

Hereditary haemorrhagic telangiectasia type 2, caused by ACVRL1 (ALK1) mutations, is complicated by brain arteriovenous malformations for which treatment options remain limited. Using endothelial-specific inducible Alk1 knockout mice and regionally resolved single-cell RNA sequencing, the authors show that loss of ALK1 signalling induces these malformations predominantly in the perineural vascular plexus. The process is driven by emergence of a KIT+ angiogenic endothelial population whose transcriptional profile mirrors human malformations, with tip-cell markers and activation of PI3K and KRAS pathways; KIT expression is conserved in endothelial cells from both sporadic and disease-related human brain AVMs. The authors demonstrate that Kit is directly repressed by BMP9-ALK1-SMAD4 signalling, and pharmacological KIT inhibition reduced angiogenic reprogramming and malformations in vivo without affecting normal vasculature.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A druggable target already covered by inhibitors available in oncology is a strong argument in a disease where embolisation and surveillance have long been all we could offer, and conserved KIT expression in sporadic malformations widens the potential scope further. Some restraint is warranted, however: prevention is demonstrated in mice and on malformations as they form, whereas the clinical question concerns lesions already established in adults. In clinic this changes nothing today in the management of an ACVRL1 carrier, but it justifies close attention to upcoming repurposing trials.

Analysis by Dr Thibaut Benquey