SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage

Menée initialement sur un patient présentant une mutation germinale du gène SAMHD1 et ayant développé une leucémie lymphocytaire chronique à l'âge de 24 ans, puis sur des échantillons prélevés dans le cadre d'un essai clinique, cette étude met en évidence le rôle joué par des mutations de SAMHD1 dans le développement de la maladie

Résumé en anglais

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTP TPH) and a nuclease that restricts HIV-1 in non-cycling cells. Germline mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal WGS study of chronic lymphocytic leukemia (CLL) we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germline SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency, reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development.