SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing 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 germ-line 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 and 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.
1021 - 1031
Adult, Autoimmune Diseases of the Nervous System, Cohort Studies, Comparative Genomic Hybridization, DNA Damage, Gene Frequency, Germ-Line Mutation, HeLa Cells, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Monomeric GTP-Binding Proteins, Nervous System Malformations, SAM Domain and HD Domain-Containing Protein 1, Young Adult