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

被引：185

作者：

Clifford, Ruth ^{[1
]}

Louis, Tania ^{[2
]}

Robbe, Pauline ^{[1
]}

Ackroyd, Sam ^{[3
]}

Burns, Adam ^{[1
]}

Timbs, Adele T. ^{[1
]}

Colopy, Glen Wright ^{[1
]}

Dreau, Helene ^{[1
]}

Sigaux, Francois ^{[4
]}

Judde, Jean Gabriel ^{[5
]}

Rotger, Margalida ^{[6
,7
]}

Telenti, Amalio ^{[6
,7
]}

Lin, Yea-Lih ^{[2
]}

Pasero, Philippe ^{[2
]}

Maelfait, Jonathan ^{[8
]}

Titsias, Michalis ^{[9
]}

Cohen, Dena R. ^{[10
]}

Henderson, Shirley J. ^{[1
]}

Ross, Mark T. ^{[11
]}

Bentley, David ^{[11
]}

Hillmen, Peter ^{[12
]}

Pettitt, Andrew ^{[13
]}

Rehwinkel, Jan ^{[8
]}

Knight, Samantha J. L. ^{[14
,15
]}

Taylor, Jenny C. ^{[14
,15
]}

Crow, Yanick J. ^{[16
]}

Benkirane, Monsef ^{[2
]}

Schuh, Anna ^{[1
]}

机构：

[1] Univ Oxford, Mol Diagnost Ctr, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England

[2] CNRS, Inst Genet Humaine, Unites Propres Rech 1142, Montpellier, France

[3] Natl Hlth Serv Fdn Trust, Bradford Teaching Hosp, Bradford, W Yorkshire, England

[4] Hop St Louis, INSERM, Lab Mol Hematol, Ctr Hayem,U462, Paris, France

[5] Xentech SAS, Genopole, Evry, France

[6] Univ Hosp Ctr, Inst Microbiol, Lausanne, Switzerland

[7] Univ Lausanne, Lausanne, Switzerland

[8] Univ Oxford, Weatherall Inst Mol Med, Radcliffe Dept Med, Med Res Council,Human Immunol Unit, Oxford, England

[9] Athens Univ Econ & Business, Athens, Greece

[10] Univ Leeds, Leeds Inst Clin Trials Res, Leeds, W Yorkshire, England

[11] Illumina Cambridge Ltd, Saffron Walden, Essex, England

[12] St James Inst Oncol, Leeds, W Yorkshire, England

[13] Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool L69 3BX, Merseyside, England

[14] Univ Oxford, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England

[15] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[16] Univ Manchester, St Marys Hosp,Fac Med & Human Sci, Cent Manchester Univ Hosp,Inst Human Dev, Natl Hlth Serv Fdn Trust,Manchester Acad Hlth Sci, Manchester M13 0JH, Lancs, England

来源：

BLOOD | 2014年 / 123卷 / 07期

基金：

英国惠康基金; 欧洲研究理事会;

关键词：

AICARDI-GOUTIERES SYNDROME; RESTRICTION FACTOR SAMHD1; HIV-1; INFECTION; MUTATIONS; CANCER; INACTIVATION; INSTABILITY; EVOLUTION; SURVIVAL; REVEALS;

D O I：

10.1182/blood-2013-04-490847

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-Goutieres 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.

引用

页码：1021 / 1031

页数：11

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