Abstract
Abstract The myeloid translocation genes (MTG) are preferred targets of chromosomal translocations with the Runx1 gene in acute myeloid leukemia (AML) pathogenesis. The resulting fusion proteins, RUNX1-MTG8 and RUNX1-MTG16, influence gene expression programs that control self-renewal and differentiation in hematopoiesis. How they engage the machinery of self-renewal to alter hematopoietic development is poorly understood. To gain additional insights into this question, we investigated structure–function relationships between RUNX1-MTG fusion proteins and core components of the Notch transcription complex, a critical determinant of cell fate specification in diverse tissues. The Notch transcription complex is composed minimally of the transcriptional repressor CSL, the intracellular domain of Notch receptors (N-ICD) and the transcriptional co-activator Mastermind (MAML). We show that RUNX1-MTG fusion proteins transactivate a Notch-responsive element from the Hes1 promoter. Using MTG16 as a model protein, we show that N-ICDs interact with a discrete domain in the MTG N-terminus. We translated these findings to the fusion proteins and found N-ICD binding was retained by RUNX1-MTGs and a RUNX1-MTG16 mutant that lacks the N1-ICD binding site. In parallel experiments, we defined the binding region for MTG proteins and their fusion protein derivatives on the N1-ICD. Informed by these structural relationships, we utilized RUNX1-MTG proteins or mutants that lack N1-ICD binding sites in transcriptional reporter assays. Our findings suggest that RUNX1-MTG fusion proteins alter transcription of the Notch target gene, Hes1 and intimate a structure–function relationship between RUNX1-MTG fusion proteins and Notch signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3905.
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