FAS deficiency in mast cell disease and autoimmune lymphoproliferative syndrome – ALMA

Mastocytosis is a heterogeneous disease characterized by an accumulation of mast cells (MCs) in the skin or various organs. The systemic form includes indolent and aggressive forms such as mast cell leukemia. Somatic mutations activating the KIT receptor tyrosine kinase (TK) are found in 90% of cases, but several arguments indicate that other genetic events are necessary to trigger the disease. We have recently demonstrated the synergistic cooperation between germline GLI3 hedgehog (Hh) mutations and somatic KIT mutations in mastocytosis onset, and have proposed a new therapeutic strategy combining anti-Hh and anti-TKs for patients overexpressing Hh genes.

Seeking other genetic events, we recently identified mastocytosis patients carrying germline mutations (stop codon FASR250X and missense FASLGH122N) in the FAS-FASLG apoptotic pathway. The deficiency of this pathway is known to be the main driver of autoimmune lymphoproliferative syndrome (ALPS) but has never been studied in mastocytosis. We also found that MCs from patients with aggressive mastocytosis express very low levels of FAS at the membrane, indicating that deregulation of FAS is involved in the pathophysiology of the disease via resistance to apoptosis.

Interestingly, 75% of ALPS patients carry germline mutations in FAS gene with variable expressivity. Mutations induce partial or total inhibition of FAS, or production of a dominant negative form that blocks apoptosis. Among the patients, 15% develop urticaria and/or severe allergies indicating that MCs are activated in this pathophysiological context.

Here, we propose to study post-transcriptional defects of FAS expression resulting from pathogenic mutations or splicing dysregulation in mastocytosis and ALPS diseases. Moreover, our collaborative work will shed light on the contribution of mast cells in ALPS.