title: Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell acute lymphoblastic leukemia.
abstract: Aberrant recombination between T-cell receptor genes and oncogenes gives rise to chromosomal translocations that are genetic hallmarks in several subsets of human T-cell acute lymphoblastic leukemias. The V(D)J recombination machinery has been shown to play a role in the formation of these T-cell receptor translocations. Other, non-T-cell receptor chromosomal aberrations, such as SIL-TAL1 deletions, have likewise been recognized as V(D)J recombination associated aberrations. Despite the postulated role of V(D)J recombination, the extent of the V(D)J recombination machinery involvement in the formation of T-cell receptor and non-T-cell receptor aberrations in T-cell acute lymphoblastic leukemia is still poorly understood. We performed a comprehensive in silico and ex vivo evaluation of 117 breakpoint sites from 22 different T-cell receptor translocation partners as well as 118 breakpoint sites from non-T-cell receptor chromosomal aberrations. Based on this extensive set of breakpoint data, we provide a comprehensive overview of T-cell receptor and oncogene involvement in T-ALL. Moreover, we assessed the role of the V(D)J recombination machinery in the formation of chromosomal aberrations, and propose an up-dated mechanistic classification on how the V(D)J recombination machinery contributes to the formation of T-cell receptor and non-T-cell receptor aberrations in human T-cell acute lymphoblastic leukemia.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Nicole S D
authors.initials: NS
authors.lastname: Larmonie
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Irene
authors.initials: I
authors.lastname: Homminga
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
mesh_terms: D000818:Animals; D056905:Chromosome Breakpoints; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D060152:V(D)J Recombination / Q000235:genetics*
chemical_list: D011948:Receptors, Antigen, T-Cell
references.citation: Cancer Res. 1994 Jan 1;54(1):226-30
references.pmid: 8261443
references.citation: J Exp Med. 2010 Jul 5;207(7):1369-80
references.pmid: 20566716
references.citation: Nat Genet. 2003 Mar;33(3):342-4
references.pmid: 12567187
references.citation: Blood. 2007 Aug 15;110(4):1251-61
references.pmid: 17452517
references.citation: Blood. 2012 Oct 18;120(16):3298-309
references.pmid: 22948044
references.citation: J Exp Med. 2005 Jun 6;201(11):1715-23
references.pmid: 15928199
references.citation: Mol Cell Biol. 1992 Oct;12(10):4751-7
references.pmid: 1406658
references.citation: Nature. 2011 Mar 3;471(7336):119-23
references.pmid: 21368836
references.citation: J Exp Med. 1988 Feb 1;167(2):682-7
references.pmid: 3162254
references.citation: EMBO J. 1990 Feb;9(2):415-24
references.pmid: 2303035
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1282-97
references.pmid: 16893685
references.citation: Leukemia. 2002 Nov;16(11):2205-12
references.pmid: 12399963
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3497-502
references.pmid: 10737801
references.citation: J Exp Med. 1992 Oct 1;176(4):919-25
references.pmid: 1402666
references.citation: Leukemia. 2006 Jul;20(7):1279-87
references.pmid: 16688224
references.citation: J Immunol. 2006 May 15;176(10):5707-12
references.pmid: 16670273
references.citation: Nucleic Acids Res. 2010 May;38(9):2944-54
references.pmid: 20139091
references.citation: J Exp Med. 1990 Nov 1;172(5):1403-8
references.pmid: 2230650
references.citation: Blood. 2007 Jul 1;110(1):388-92
references.pmid: 17360939
references.citation: Haematologica. 2012 Feb;97(2):258-61
references.pmid: 22058201
references.citation: BMC Genomics. 2009 Jul 24;10:335
references.pmid: 19630943
references.citation: Leukemia. 1999 Jun;13(6):975-9
references.pmid: 10360388
references.citation: J Exp Med. 1989 Feb 1;169(2):369-77
references.pmid: 2536065
references.citation: J Exp Med. 1991 Oct 1;174(4):867-73
references.pmid: 1680958
references.citation: J Clin Invest. 1991 Jun;87(6):2029-35
references.pmid: 2040693
references.citation: J Immunol. 1997 Nov 1;159(9):4341-9
references.pmid: 9379030
references.citation: Curr Opin Immunol. 2001 Apr;13(2):186-94
references.pmid: 11228412
references.citation: J Exp Med. 1990 Aug 1;172(2):409-18
references.pmid: 1695665
references.citation: Genes Chromosomes Cancer. 2009 Aug;48(8):725-36
references.pmid: 19455608
references.citation: J Exp Med. 2002 Jan 7;195(1):85-98
references.pmid: 11781368
references.citation: Cell. 1991 Aug 23;66(4):649-61
references.pmid: 1831692
references.citation: Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11416-20
references.pmid: 1763056
references.citation: Oncogene. 1988 Feb;2(2):195-200
references.pmid: 2966921
references.citation: Haematologica. 2006 Mar;91(3):317-21
references.pmid: 16531254
references.citation: Leukemia. 2009 May;23(5):1003-6
references.pmid: 19151773
references.citation: Blood. 2006 Jul 1;108(1):305-10
references.pmid: 16507772
references.citation: Cancer Res. 2005 Aug 15;65(16):7151-8
references.pmid: 16103065
references.citation: Leukemia. 2006 Jan;20(1):82-6
references.pmid: 16270038
references.citation: EMBO J. 2003 Mar 17;22(6):1381-8
references.pmid: 12628930
references.citation: Nat Methods. 2009 Nov;6(11):837-42
references.pmid: 19820713
references.citation: Genes Chromosomes Cancer. 1989 Sep;1(1):15-22
references.pmid: 2535034
references.citation: Proc Natl Acad Sci U S A. 1989 Jun;86(11):4161-5
references.pmid: 2542965
references.citation: Cell. 2004 Apr 16;117(2):171-84
references.pmid: 15084256
references.citation: Leukemia. 2006 Jun;20(6):1184-7
references.pmid: 16572206
references.citation: Cell. 1987 Jul 3;50(1):107-17
references.pmid: 3036364
references.citation: Cell. 2010 Apr 30;141(3):400-2
references.pmid: 20434980
references.citation: Blood. 1989 Jul;74(1):374-9
references.pmid: 2526665
references.citation: EMBO J. 1988 Jul;7(7):2011-7
references.pmid: 3416831
references.citation: Mol Cell Biol. 2002 May;22(9):3174-7
references.pmid: 11940674
references.citation: Mol Biol Evol. 2001 Jun;18(6):1139-42
references.pmid: 11371603
references.citation: Nat Struct Mol Biol. 2011 Jul 03;18(8):950-5
references.pmid: 21725294
references.citation: N Engl J Med. 2002 Nov 14;347(20):1593-603
references.pmid: 12432047
references.citation: Nat Rev Immunol. 2011 Apr;11(4):251-63
references.pmid: 21394103
references.citation: EMBO J. 1991 Oct;10(10):2905-10
references.pmid: 1717256
references.citation: Mol Cell Biol. 1989 May;9(5):2124-32
references.pmid: 2501659
references.citation: J Exp Med. 1993 Apr 1;177(4):965-77
references.pmid: 8459224
references.citation: Cancer Genet Cytogenet. 1990 Jan;44(1):47-54
references.pmid: 1967157
references.citation: Blood. 2006 Nov 15;108(10):3520-9
references.pmid: 16873670
references.citation: Leukemia. 2005 Feb;19(2):201-8
references.pmid: 15668700
references.citation: Leukemia. 2008 Jun;22(6):1266-7
references.pmid: 17989714
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1049-64
references.pmid: 16807138
references.citation: Blood. 1989 May 1;73(6):1672-6
references.pmid: 2523742
references.citation: Somat Cell Mol Genet. 1995 Sep;21(5):309-26
references.pmid: 8619128
references.citation: J Immunol. 2006 Nov 1;177(9):6038-43
references.pmid: 17056529
references.citation: Blood. 1992 Mar 1;79(5):1327-33
references.pmid: 1311214
references.citation: Cancer Cell. 2002 Feb;1(1):75-87
references.pmid: 12086890
references.citation: Hum Mutat. 2006 Aug;27(8):829
references.pmid: 16835902
references.citation: Leukemia. 1993 Oct;7(10):1509-13
references.pmid: 8412312
references.citation: Blood. 2005 Jul 1;106(1):274-86
references.pmid: 15774621
references.citation: Oncogene. 1998 Oct 8;17(14):1787-95
references.pmid: 9778044
references.citation: Blood. 1992 Dec 15;80(12):3189-97
references.pmid: 1281693
references.citation: Leukemia. 2006 Sep;20(9):1496-510
references.pmid: 16826225
references.citation: J Biol Chem. 2001 Aug 3;276(31):29126-33
references.pmid: 11390401
references.citation: Blood. 1993 Apr 15;81(8):2110-7
references.pmid: 8471769
references.citation: J Med Genet. 1996 Feb;33(2):153-6
references.pmid: 8929954
references.citation: EMBO J. 1988 Feb;7(2):385-94
references.pmid: 3259177
references.citation: Cancer Res. 1991 Nov 1;51(21):6001-5
references.pmid: 1933863
references.citation: Am J Hum Genet. 2008 Feb;82(2):320-32
references.pmid: 18252213
references.citation: Science. 1986 Nov 21;234(4779):982-5
references.pmid: 3490692
references.citation: Immunity. 2006 Jul;25(1):31-41
references.pmid: 16860755
references.citation: Biochem J. 2012 Nov 15;448(1):115-25
references.pmid: 22891626
references.citation: Blood. 1994 Aug 15;84(4):1232-6
references.pmid: 8049439
references.citation: Genes Chromosomes Cancer. 1997 Dec;20(4):363-71
references.pmid: 9408752
references.citation: Proc Natl Acad Sci U S A. 1989 Jul;86(13):5039-43
references.pmid: 2740341
references.citation: Cell Mol Life Sci. 2010 Jan;67(1):43-62
references.pmid: 19727556
references.citation: J Exp Med. 1990 Feb 1;171(2):489-501
references.pmid: 2303782
references.citation: DNA Repair (Amst). 2006 Sep 8;5(9-10):1246-58
references.pmid: 16798110
references.citation: Blood. 1991 Nov 15;78(10):2686-95
references.pmid: 1824262
references.citation: Cancer Cell. 2012 Apr 17;21(4):563-76
references.pmid: 22516263
references.citation: Blood. 1999 Jun 15;93(12):4079-85
references.pmid: 10361104
references.citation: Annu Rev Genet. 1997;31:635-62
references.pmid: 9442910
references.citation: Proc Natl Acad Sci U S A. 1990 Apr;87(8):3161-5
references.pmid: 2326274
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W262-7
references.pmid: 20478831
references.citation: Blood. 2004 Jan 15;103(2):442-50
references.pmid: 14504110
references.citation: Blood. 2012 Jul 26;120(4):789-99
references.pmid: 22709691
references.citation: Cancer Cell. 2011 Apr 12;19(4):484-97
references.pmid: 21481790
references.citation: Cell. 1988 Apr 8;53(1):137-44
references.pmid: 3258192
references.citation: Curr Top Microbiol Immunol. 1999;246:205-13; discussion 214-5
references.pmid: 10396058
references.citation: J Exp Med. 2010 Dec 20;207(13):2809-16
references.pmid: 21115692
references.citation: Proc Natl Acad Sci U S A. 1989 Mar;86(6):2031-5
references.pmid: 2467296