Wnt signaling induces transcription, spatial proximity, and translocation of fusion gene partners in human hematopoietic cells

• Published in: Blood Vol. 126; no. 15; pp. 1785 - 1789
• Main Authors: Ugarte, Giorgia D., Vargas, Macarena F., Medina, Matías A., León, Pablo, Necuñir, David, Elorza, Alvaro A., Gutiérrez, Soraya E., Moon, Randall T., Loyola, Alejandra, De Ferrari, Giancarlo V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.10.2015
• Subjects: beta Catenin - genetics; Cells, Cultured; Chromosome Aberrations; Chromosomes, Human, Pair 21 - genetics; Chromosomes, Human, Pair 8 - genetics; Core Binding Factor Alpha 2 Subunit - genetics; Fluorescent Antibody Technique; Gene Expression Regulation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; In Situ Hybridization, Fluorescence; Oncogene Proteins, Fusion - genetics; Proto-Oncogene Proteins - genetics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RUNX1 Translocation Partner 1 Protein; Signal Transduction; Transcription Factors - genetics; Translocation, Genetic - genetics; Wnt Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-04-638494

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/β-catenin signaling increases the expression of ETO and RUNX1 genes in human hematopoietic progenitors. We found that β-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/β-catenin signaling induces transcription and translocation of RUNX1 and ETO fusion gene partners, opening a novel window to understand the onset/development of leukemia. •Wnt/β-catenin signaling increases ETO and Runx1 transcription in human hematopoietic progenitors.•Wnt/β-catenin signaling enhances spatial proximity of ETO and RUNX1 genes and induces the generation of a recurrent translocation event.