Analysis of the association of Notch pathway genes with ID4 and Ikaros gene expression in

leukemia
Nejat Dalay, Orkun Gurbuz. Istanbul Univ. Oncology Inst., Istanbul, Turkey
The Notch signal pathway plays an important role in several cellular processes in a variety of tissues.
In the hematopoiesis Notch expression is involved in various aspects of cellular regulation and
aberrant Notch signaling components have been associated with malignant transformation.
Hes1 (hairy/enhancer of split 1) gene is a Notch target gene coding for a transcriptional repressor
that is necessary to maintain progenitor cell populations. HES1 can bind promoter regions of the
cyclin-dependent kinase inhibitors and repress their expression. Hes-1 expression can be stimulated
by growth factors
The Hey family of transcriptional repressors are canonical direct targets of Notch and function as
downstream effectors of Notch signaling. Expression of HES1 and HEY proteins can vary in different
cell types suggesting an additional mechanism of transcription regulation.
Ikaros is a member of the Kruppel transcription factor family. Expression of Ikaros down-regulates
expression of the Notch target genes. Deregulation of Ikaros and Notch signalling cooperate to
promote leukemogenesis, providing evidence that they function in converging pathways.
The ID4 (inhibitor of differentiation 4) gene is a member of the family of ID helix-loop-helix proteins
that function as dominant negative regulators of basic transcription factors. In certain cancer types
downregulation of the ID4 gene has been reported resulting in low or no expression of the ID4
protein.
In the current study the expression of the Hes1, Hey1, Ikaros and ID4 genes was investigated in 110
patients with acute and chronic leukemias and 32 healthy controls by real time PCR using the Ct
method.
Both Hes1 and Hey1 expression levels were significantly increased in the patients in all disease
groups. ID4 expression was significantly decreased in % 86.4 of the patients. Expression of these
genes was strongly associated. Expression of the Ikaros gene decreased only in the subgroup of
patients with CML while it increased in patients with acute leukemias and CLL.
Our data suggest that the Notch pathway genes Hes1 and Hey1 are activated in leukemias and may
contribute to the disease development while the ID4 gene is supressed, possibly by methylation.