Alternative Splice Variants Modulates Dominant-Negative Function of Helios in T-Cell Leukemia.
The molecular defects which lead to multistep incidences of human T-cell leukemia have yet to be identified. The DNA-binding protein Helios (known as IKZF2), a member of the Ikaros family of Krüppel-like zinc-finger proteins, functions pivotally in T-cell differentiation and activation. In this study, we identify three novel short Helios splice variants which are T-cell leukemic specific, and demonstrate their dominant-negative function. We then test the cellular localization of distinct Helios isoforms, as well as their capability to form heterodimer with Ikaros, and the association with complexes comprising histone deacetylase (HDAC). In addition, the ectopic expression of T-cell leukemic Helios isoforms interferes with T-cell proliferation and apoptosis. The gene expression profiling and pathway analysis indicated the enrichment of signaling pathways essential for gene expression, translation, cell cycle checkpoint, and response to DNA damage stimulus. These data indicate the molecular function of Helios to be involved in the leukemogenesis and phenotype of T-cell leukemia, and also reveal Helios deregulation as a novel marker for T-cell leukemia.
Department of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.
Shaorong
S
Zhao
Tianjin Entry-Exit Inspection and Quarantine Bureau, Tianjin 300308, China.
Wei
W
Liu
Department of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.
Yinghui
Y
Li
Department of Hematology, First-Central Hospital, Tianjin 300060, China.
Pengjiang
P
Liu
Department of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.
Shufang
S
Li
State Key Laboratory of Medical Chemical Biology, Tianjin 300070, China.
Daolei
D
Dou
Department of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.
Yue
Y
Wang
Department of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.
Rongcun
R
Yang
Department of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.|Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin 300071, China.
Rong
R
Xiang
Department of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.
Feifei
F
Liu
Leukemia. 2010 Jul;24(7):1290-8
20508609
Leukemia. 2015 Jun;29(6):1301-11
25655195
Leuk Res. 2011 Apr;35(4):448-58
20684991
Nucleic Acids Res. 2009 Jan;37(Database issue):D674-9
18832364
Leukemia. 2010 Jul;24(7):1258-64
20445578
Br J Haematol. 2003 Apr;121(1):165-9
12670348
Nature. 2015 Oct 22;526(7574):525-30
26466571
J Exp Med. 2013 Feb 11;210(2):269-85
23337809
Immunity. 1999 Mar;10(3):345-55
10204490
Genes Dev. 1998 Mar 15;12(6):782-96
9512513
Blood. 2015 Jan 15;125(3):504-15
25370416
PLoS One. 2011;6(6):e20731
21677778
Nat Immunol. 2014 Mar;15(3):294-304
24509510
Science. 2015 Oct 16;350(6258):334-9
26472910
Immunol Rev. 2015 Jan;263(1):257-78
25510282
Cancer Sci. 2013 Aug;104(8):1097-106
23600753
N Engl J Med. 2009 Jan 29;360(5):524-6
19131438
Mol Immunol. 2010 Apr;47(7-8):1595-600
20226531
Blood. 2007 Mar 1;109(5):2190-7
17110463
Immunol Cell Biol. 2003 Jun;81(3):171-5
12752680
Nature. 2008 May 1;453(7191):110-4
18408710
Biochem Biophys Res Commun. 2011 Mar 18;406(3):430-4
21329675
J Cell Biol. 2010 Sep 6;190(5):741-9
20805320
Mol Cell Biol. 2005 Oct;25(19):8415-29
16166625
J Neurosci Res. 2009 Dec;87(16):3521-34
19598246
Cell. 1995 Oct 20;83(2):289-99
7585946
J Immunol. 2012 Feb 1;188(3):976-80
22198953
Nat Immunol. 2013 Oct;14(10):1073-83
24013668
Curr Opin Immunol. 2010 Apr;22(2):154-60
20299195
Proc Natl Acad Sci U S A. 2012 Oct 30;109 (44):18072-7
23071339
Nat Immunol. 2006 Apr;7(4):382-91
16518393
Cancer Sci. 2007 Feb;98(2):182-8
17297655
J Immunol. 2006 Mar 15;176(6):3593-602
16517728
J Immunol. 2001 Aug 15;167(4):1867-70
11489963
Oncogene. 2016 May 12;35(19):2413-27
26300000
J Cell Sci. 2007 Aug 1;120(Pt 15):2619-30
17646674
Blood. 2001 Nov 1;98(9):2673-80
11675337
Curr Biol. 1998 Apr 23;8(9):508-15
9560339
EMBO J. 1999 Jun 1;18(11):3090-100
10357820
Blood. 2002 Feb 15;99(4):1350-5
11830486
Nature. 2011 May 12;473(7346):230-3
21562564
Int J Hematol. 2014 Sep;100(3):220-9
25085254
Eur J Immunol. 2014 Jul;44(7):2048-58
24740292
Mol Cell Biol. 1994 Dec;14(12):8292-303
7969165
Nat Immunol. 2011 Jan;12(1):86-95
21131965
Leukemia. 2011 Feb;25(2):254-8
21102428
J Immunol. 2013 Feb 1;190(3):1008-16
23275607
Mol Cell Biol. 2000 Oct;20(20):7572-82
11003653
Cell. 1994 Oct 7;79(1):143-56
7923373
Immunity. 2010 Nov 24;33(5):685-98
21093322