The RUNX1 gene, located in chromosome 21q22, is crucial for the establishment of definitive hematopoiesis and the generation of hematopoietic stem cells in the embryo. It contains a 'Runt homology domain' as well as transcription activation and inhibition domains. RUNX1 can act as activator or repressor of target gene expression depending upon the large number of transcription factors, coactivators and corepressors that interact with it. Translocations involving chromosomal band 21q22 are regularly identified in leukemia patients. Most of them are associated with a rearrangement of RUNX1. Indeed, at present, 55 partner chromosomal bands have been described but the partner gene has solely been identified in 21 translocations at the molecular level. All the translocations that retain Runt homology domains but remove the transcription activation domain have a leukemogenic effect by acting as dominant negative inhibitors of wild-type RUNX1 in transcription activation.