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 Qazi1,2 , Zahide Ozer1 , Cheney Mao3 , Fatih Uckun1,4,5
1. Systems Immunobiology Laboratory and Developmental Therapeutics Program, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Los Angeles, CA, USA
2. Department of Biology and Bioinformatics Program, Gustavus Adolphus College, 800 W College Avenue, St. Peter, MN 56082, USA
3. Viva Biotech, Chicago, IL 60612, USA
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, USA
Author    Correspondence author
International Journal of Molecular Medical Science, 2014, Vol. 4, No. 1   doi: 10.5376/ijmms.2014.04.0001
Received: 06 Nov., 2013    Accepted: 10 Dec., 2013    Published: 31 Dec., 2013
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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.1-18 (doi: 10.5376/ijmms.2013.04.0001)

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
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