Abstract A20: Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL and menin
Ewing sarcoma is driven by the oncogenic fusion protein, EWS-FLI1, and arises via de-regulation of developmental transcriptional programs. Control of normal developmental transcription programs is governed by epigenetic regulation which, in the case of HOX programs, is dependent on coordinated and reciprocal actions of polycomb (PcG) and trithorax (TrxG) proteins. We recently reported that in Ewing sarcoma posterior HOX genes, in particular HOXD13, are abnormally over-expressed and that the promoters of these genes are marked with the TrxG-dependent activating histone modification, H3K4me3. H3K4me3 is deposited by the MLL methyltransferase, a key enzyme that is frequently mutated in leukemia, largely as a result of chromosomal translocations that induce the creation of oncogenic MLL fusion-proteins. In leukemia, MLL fusion-proteins cooperate with wild-type MLL and the scaffolding protein menin to induce malignant transformation via deregulation of HOXA genes. The purpose of this study was to test the hypothesis that MLL and menin contribute to tumorigenesis and to posterior HOX gene deregulation in Ewing sarcoma. Gene and protein expression were determined by microarray, qRT-PCR, western blot and immunohistochemistry. Loss of function was achieved by lentiviral shRNAs and by exposing cells to MI-503, a small molecule inhibitor of menin-MLL protein-protein interactions. Changes in gene and protein expression after MI-503 treatment were assessed by qRT-PCR and western blot. Chr...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Svoboda, L. K., Bailey, N., Krook, M., Noord, R. V., Harris, A., Patel, R. M., Thomas, D., Cierpicki, T., Grembecka, J., Lawlor, E. R. Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research
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