The British journal of dermatology · 2025
Exploration of the mutational landscape of cutaneous leiomyoma confirms FH as a driver gene and identifies targeting purine metabolism as a potential therapeutic strategy.
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van der Weyden Louise, Del Castillo Velasco-Herrera Martin, Cheema Saamin, Wong Kim, Boccacino Jacqueline M, Vermes Ian, Offord Victoria, Droop Alastair, Jones David R A, Anderson Elizabeth, Hardy Claire, de Saint Aubain Nicolas, Ferguson Peter M, Mogler Carolin, Rajan Neil, Frew Derek, Harms Paul W, Billings Steven D, Schatton Désirée, Segarra-Mondejar Marc, Arends Mark J, Ferreira Ingrid, Brenn Thomas, Frezza Christian, Adams David J
Аннотация
To comprehensively explore the mutational landscape of cutaneous leiomyoma (cLM) and identify candidate driver events, we performed a retrospective, multi-institutional, whole-exome sequencing and RNA sequencing study. We confirmed that a large proportion of patients with cLM have germline FH variants and additionally showed that somatic alteration of FH also drives cLM, with biallelic inactivation of FH being a frequent event. Treatment of Fh1-proficient and -deficient cell lines with the purine antagonist and chemotherapeutic agent, mercaptopurine, significantly decreased growth/colony formation; however, the addition of nucleosides was able to rescue only the Fh1-proficient cells, suggesting that purine metabolism is a targetable vulnerability for FH-deficient cLMs.