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.
Published Version
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