Abstract 4203: Analysis of the association of Notch pathway genes with ID4 and Ikaros gene expression in leukemia

Abstract

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 ΔΔCt 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4203. doi:1538-7445.AM2012-4203