RUNX1 translocations in malignant hemopathies

The RUNX gene family includes three evolutionarily conserved genes (RUNX1, RUNX2 and RUNX3) encoding transcription factors involved in cell lineage differentiation during development and various forms of cancer. The RUNX1 gene, located in chromosome 21q22, is crucial for the establishment of definite hematopoiesis and the generation of hematopoietic stem cells in the embryo. It contains a "Runt homology domain" (RHD) and a transactivation domain. 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. Three modes of leukemogenesis due to acquired alterations of the RUNX1 gene have been recognized: point mutations, amplification and translocations. Some translocations have been shown to be recurrent whereas others have been only reported in a few cases or in a sole case. At present, 32 partner chromosomes have been described but the partner gene has solely been identified in 17 translocations at the molecular level. Most of the translocations involving RUNX1 lead to the formation of a fusion transcript made of the 5' region of RUNX1, including the RHD, fused to the 3' region of a partner gene, with the exception of RUNX1-ETV6 in which the 3' sequences of RUNX1, including the RHD, are fused to the 5' region of ETV6, including its promotor. Three RUNX1 translocations (retaining RHD) that are fused out of frame to partner genes are also known. All the translocations that retain RHD but remove the transcription activation domain have a leukemogenic effect by acting as dominant negative inhibitors of wild-type RUNX1 in transcription activation.