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International Journal of Molecular Medical Science
2014, Vol. 4, No.1, 1-16
http://ijmms.sophiapublisher.com
Research Report
Open Access
Leukemic T-cell Precursors from T-lineage All Patients Are Characterized by
Profound Ku80 Deficiency as well as Functional IK Deficiency with Very Low
Ikaros Target Gene Expression Levels
Sanjive Qazi
1,2
, Zahide Ozer
1
, Cheney Mao
3
, Fatih M. Uckun
1,4,5
1. Systems Immunobiology Laboratory and Developmental Therapeutics Program, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los
Angeles, Los Angeles, CA
2. Department of Biology and Bioinformatics Program, Gustavus Adolphus College, 800 W College Avenue, St. Peter, MN 56082
3. Viva Biotech, Chicago, IL 60612
4. Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA
5. Developmental Therapeutics Program, USC Norris Comprehensive Cancer Center, Los Angeles, CA 90089
Correspondings author: fmuckun@chla.usc.edu;
Authors;
International Journal of Molecular Medical Science, 2014, Vol.4, No.1 doi: 10.5376/ijmms.2014.04.0001
Copyright
© 2014 Uckun et al. This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
We recently found that Ku regulates Ikaros (IK) function and Ku deficiency causes a lymphoproliferative disorder of
thymic T-cell precursors with functional IK deficiency. We now examined the expression levels of validated IK target genes that
harbor IK binding sites in primary leukemic cells from 1 104 pediatric ALL patients in relationship to Ku expression levels.
Hierarchical cluster analysis of cellular gene expression profiles revealed a highly significant correlation between Ku expression
level and expression levels of validated IK target genes. Notably, the expression levels of 12 IK-regulated lymphoid priming genes
were significantly upregulated in human lymphocyte precursor cells from primary bone marrow specimens of pediatric patients with
ALL expressing high levels of Ku. The observed striking Ku-dependency of the IK target gene expression levels taken together with
the results of our earlier RNAi experiments indicate that IK function in human lymphocyte precursors is controlled by Ku expression
levels. Leukemic T-cell precursors from children with T-lineage ALL were characterized by profoundly diminished Ku80 transcript
levels as well as functional IK deficiency with very low IK target gene expression levels. These results extend our previous studies in
mice and indicate that Ku-deficiency is also a contributor to the functional IK-deficiency in pediatric T-lineage ALL.
Keywords
Ikaros (IK); T-cell precursors; IK deficiency
Introduction
Zinc finger (ZF) proteins contain multiple cysteine
(Cys) and/or histidine (His) residues and use zinc
coordination to stabilize their folding. The Cys2His2
ZF is the most prevalent protein motif in mammalian
cells and defines the largest
family of
sequence-specific DNA binding proteins. Many DNA
binding proteins contain several ZF that make tandem
contacts along the target DNA segment. Cys2His2 ZF
domains participate in protein-DNA, protein-RNA as
well as protein-protein interactions (Coleman, 1992;
Klug and Schwabe, 1995; Mackay et al., 1998;
Nardelli et al., 1992). Ikaros (IK) is a ZF-containing
sequence-specific DNA binding protein that plays a
pivotal role in immune homeostasis through
transcriptional regulation of the earliest stages of
lymphocyte ontogeny and differentiation by both (a)
gene transcriptional
activation via efficient
transcription initiation as well as elongation and (b)
repression (Georgopoulos, 2002; Cobbs et al., 2000;
Thompson et al., 2007; Merkenschlager, 2010;
Yoshida et al., 2010; Bottardi et al., 2011). IK is a
pleotropic protein with important regulatory functions
in gene silencing, DNA replication and genomic
Molecular Medical Science, Int’l Journal of
Preferred citation for this article:
Uckun et al., 2014, Leukemic T-cell Precursors from T-lineage All Patients Are Characterized by Profound Ku80 Deficiency as well as Functional IK
Deficiency with Very Low Ikaros Target Gene Expression Levels, Vol.4, No.1 pp.1-16 (doi: 10.5376/ijmms.2014.04.0001)
Received: 06 Nov., 2013
|
Accepted: 10 Dec., 2013
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Published: 31 Dec., 2013