Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma

Menée à l'aide de lignées cellulaires, d'un modèle murin ainsi que d'échantillons sanguins et d'échantillons de tissus ganglionnaires issus de patients atteints d'un lymphome anaplasique à grandes cellules B ALK+, cette étude identifie des mutations somatiques récurrentes au niveau des gènes codant pour les cadhérines de la famille FAT ou du facteur de transcription RUNX1T1 et met en évidence l'effet de ces mutations sur le phénotype de la maladie et le pronostic

Résumé en anglais

Background : Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory.

Methods : We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models.

Results : Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the