Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc

被引:59
作者
Unniraman, S
Zhou, SM
Schatz, DG
机构
[1] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA
关键词
D O I
10.1038/ni1127
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Chromosomal translocations involving immunoglobulin heavy chain (Igh) switch regions and an oncogene such as Myc represent initiating events in the development of many B cell malignancies. These translocations are widely thought to result from aberrant class-switch recombination. To test this model, we measured translocations in mice deficient in activation-induced cytidine deaminase (AID) that lack class-switch recombination. We found that AID made no measurable contribution to the generation of initial translocations, indicating that the intrinsic fragility of the switch regions or a pathway unrelated to AID is responsible for these translocations. In contrast, the outgrowth of translocation-positive cells was dependent on AID, raising the possibility that AID is important in tumor progression, perhaps by virtue of its mutagenic properties.
引用
收藏
页码:1117 / 1123
页数:7
相关论文
共 61 条
[1]  
BAAR J, 1995, J IMMUNOL, V155, P1911
[2]   Chromosome translocations in multiple myeloma [J].
Bergsagel, PL ;
Kuehl, WM .
ONCOGENE, 2001, 20 (40) :5611-5622
[3]   DNA double-strand breaks: Prior to but not sufficient in targeting hypermutation [J].
Bross, L ;
Muramatsu, M ;
Kinoshita, K ;
Honjo, T ;
Jacobs, H .
JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 195 (09) :1187-1192
[4]   DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation [J].
Bross, L ;
Fukita, Y ;
McBlane, F ;
Démollière, C ;
Rajewsky, K ;
Jacobs, H .
IMMUNITY, 2000, 13 (05) :589-597
[5]   The block in immunoglobulin class switch recombination caused by activation-induced cytidine deaminase deficiency occurs prior to the generation of DNA double strand breaks in switch μ region [J].
Catalan, N ;
Selz, F ;
Imai, K ;
Revy, P ;
Fischer, A ;
Durandy, A .
JOURNAL OF IMMUNOLOGY, 2003, 171 (05) :2504-2509
[6]   Transcription-targeted DNA deamination by the AID antibody diversification enzyme [J].
Chaudhuri, J ;
Tian, M ;
Khuong, C ;
Chua, K ;
Pinaud, E ;
Alt, FW .
NATURE, 2003, 422 (6933) :726-730
[7]   Class-switch recombination: Interplay of transcription, DNA deamination and DNA repair [J].
Chaudhuri, J ;
Alt, FW .
NATURE REVIEWS IMMUNOLOGY, 2004, 4 (07) :541-552
[8]   Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification [J].
Difilippantonio, MJ ;
Petersen, S ;
Chen, HT ;
Johnson, R ;
Jasin, M ;
Kanaar, R ;
Ried, T ;
Nussenzweig, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 196 (04) :469-480
[9]   Internal IgH class switch region deletions are position-independent and enhanced by AID expression [J].
Dudley, DD ;
Manis, JP ;
Zarrin, AA ;
Kaylor, L ;
Tian, M ;
Alt, FW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (15) :9984-9989
[10]   Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA [J].
Duquette, ML ;
Handa, P ;
Vincent, JA ;
Taylor, AF ;
Maizels, N .
GENES & DEVELOPMENT, 2004, 18 (13) :1618-1629