title: SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage.
abstract: 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.
authors: Oxford National Institute for Health Research Biomedical Research Centre/Molecular Diagnostic Centre, University of Oxford, Oxford, United Kingdom;
authors: Ruth
authors: R
authors: Clifford
authors: Tania
authors: T
authors: Louis
authors: Pauline
authors: P
authors: Robbe
authors: Sam
authors: S
authors: Ackroyd
authors: Adam
authors: A
authors: Burns
authors: Adele T
authors: AT
authors: Timbs
authors: Glen
authors: G
authors: Wright Colopy
authors: Helene
authors: H
authors: Dreau
authors: Francois
authors: F
authors: Sigaux
authors: Jean Gabriel
authors: JG
authors: Judde
authors: Margalida
authors: M
authors: Rotger
authors: Amalio
authors: A
authors: Telenti
authors: Yea-Lih
authors: YL
authors: Lin
authors: Philippe
authors: P
authors: Pasero
authors: Jonathan
authors: J
authors: Maelfait
authors: Michalis
authors: M
authors: Titsias
authors: Dena R
authors: DR
authors: Cohen
authors: Shirley J
authors: SJ
authors: Henderson
authors: Mark T
authors: MT
authors: Ross
authors: David
authors: D
authors: Bentley
authors: Peter
authors: P
authors: Hillmen
authors: Andrew
authors: A
authors: Pettitt
authors: Jan
authors: J
authors: Rehwinkel
authors: Samantha J L
authors: SJ
authors: Knight
authors: Jenny C
authors: JC
authors: Taylor
authors: Yanick J
authors: YJ
authors: Crow
authors: Monsef
authors: M
authors: Benkirane
authors: Anna
authors: A
authors: Schuh
mesh_terms: D000328:Adult; D020274:Autoimmune Diseases of the Nervous System / Q000150:complications / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004249:DNA Damage / Q000235:genetics*; D005787:Gene Frequency; D018095:Germ-Line Mutation; D006367:HeLa Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000150:complications / Q000235:genetics*; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009421:Nervous System Malformations / Q000150:complications / Q000235:genetics; D000076106:SAM Domain and HD Domain-Containing Protein 1; D055815:Young Adult
chemical_list: D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins