Autoregulation of RUNX1 Activity by Homodimerization.

RUNX1 also known as AML1 is a transcription factor essential for normal hematopoiesis, platelet production and thymocyte development. RUNX1 is the most frequent target of chromosomal translocations and acquired or inherited point mutations associated with human leukemia. RUNX1 is a DNA-binding transcription factor that can act both as an activator and a repressor of gene expression depending probably on the association of RUNX1 with co-activator or corepressors in large transcription complexes at promoter sites. The C-terminus of RUNX1 contains an inhibitory region, ID, which represses positive regulation of RUNX1-dependent genes. Thus, this region could potentially act as a switch and co-operate with RUNX1-interacting transcription factors in the choice between gene activation or gene repression. Here we have examined the role of ID in gene regulation by RUNX1. We found that this region is a homo-dimerization motif that controls RUNX1-RUNX1 interaction in vitro and in vivo. The association of RUNX1 with itself through this domain appears to reduce the positive transactivating potential of RUNX1 and, if provided in trans, this domain can repress by itself the activity of RUNX1 in reporter gene assays. Our studies suggest that RUNX1 autoregulates itself through its ability to form a homodimer. Data will be shown on the effects of the ID region in hematopoietic differentiation of cell lines. The results indicate that the ID region plays critical role in RUNX1 activity and is essential to control the correct execution of hematopoietic programs. It is of importance that aside from the t(12;21), all chromosomal translocations and virtually all point mutations associated with leukemia profoundly affect the integrity of the C-terminus including the ID region. These studies suggest a novel pathway involved in RUNX1 leukemogenesis and provide new targets for the management of RUNX1-leukemia. Kislay Sinha and Donglan Li contributed equally to this study.