Wnt Signaling Induces Transcription, Spatial Proximity, And Translocation Of Fusion Gene Partners In Human Hematopoietic Cells

Chromosomal translocations are frequently associated with a wide variety of cancers, particularly hematologic malignancies. A recurrent chromosomal abnormality in acute myeloid leukemia is the reciprocal translocation t(8; 21) that fuses RUNX1 and ETO genes. We report here that Wnt/beta-catenin signaling increases the expression of ETO and RUNX1 genes in human hematopoietic progenitors. We found that beta-catenin is rapidly recruited into RNA polymerase II transcription factories (RNAPII-Ser5) and that ETO and RUNX1 genes are brought into close spatial proximity upon Wnt3a induction. Notably, long-term treatment of cells with Wnt3a induces the generation a frequent RUNX1-ETO translocation event. Thus, Wnt/beta-catenin signaling induces transcription and translocation of RUNX1 and ETO fusion gene partners, opening a novel window to understand the onset/development of leukemia.