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International Journal of Molecular Medical Science
8
in high
Ku
samples. Cluster representation of the
expression values in standard deviation units revealed
two sub-clusters of co-regulated genes:
FGFR4
,
IL13
and
VIPR1
; and 2 transcripts of
IL4
co-regulated with
STAT4
. The most discriminating differentially
expressed
IK1
target gene was
STAT4
(Z-score: 0.926,
P=2.7×10
-6
) (Figure 4, Panel B). Correlation analysis
revealed highly significant (P<0.0001) positive
relationships between
Ku
expression and 6 IK1 target
transcripts (both
FGRFR4
transcripts, both
IL4
transcripts,
STAT4
,
IL10
) with correlation co-efficients
ranging from 0.21 to 0.31.
IL5
(r=0.19; P=0.0004) and
IL13
(r=0.14; p=0.007) exhibited significant but lower
correlation coefficients. The observed striking
Ku-dependency of the IK target gene expression
levels taken together with the results of our
earlier RNAi experiments (Ozer et al., 2013)
indicate that IK function in human lymphocyte
precursors is controlled in part by
Ku
expression levels.
Figure 4 Effects of
Ku
Expression Levels on Expression Levels of
Ikaros
Target Genes in Primary Lymphocyte Precursors fromALLPatients
Note: Gene Pattern (http://www.broadinstitute.org/cancer/software/genepattern/) was used to extract expression values for the 7
IK-regulated signaling genes (35-40) in the combined data set from 4 studies with a total of 354 primary leukemia samples for further
analysis. Gene expression values for 3
Ku
transcripts and 9
Ikaros
targets from 4 published studies examining 354 ALL patient
samples (GSE3912, GSE18497, GSE4698 and GSE7440) were rank ordered according to the mean expression of the 3
Ku
transcripts.
The gene expression profiles of samples with high
Ku
expression were compared to those of samples with low
Ku
expression using a
2-sample T-test (Unequal variances). For each study, the Z-score values were calculated as the SD units from the study mean for all
the patients. The datasets were combined to test for consistent differences in the Z-scores for high
Ku
(>0.75 SD units; N=67 samples)
and low Ku (<0.75 SD units; N = 70 samples) groups. For each study the expression values were mean centered with respect to the
average expression for each gene transcript taken at diagnosis. A one-way agglomerative hierarchical clustering technique was used
to organize expression patterns using the average distance linkage method such that genes (rows) having similar expression across
patients were grouped together (average distance metric). Dendrograms were drawn to illustrate similar gene-expression profiles
from joining pairs of closely related gene expression profiles, whereby genes joined by short branch lengths showed most similarity
in expression profile across patients. The heat map represents the color-coded expression value for 67 samples with high
Ku
expression reported as mean centered expression value relative to log10 transformed expression values for 70 samples with low
Ku
expression values
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