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/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.
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP) Center for Genome Regulation, Santiago, Chile;
Giorgia D
GD
Ugarte
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP) Center for Genome Regulation, Santiago, Chile;
Macarena F
MF
Vargas
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile;
Matías A
MA
Medina
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP) Center for Genome Regulation, Santiago, Chile;
Pablo
P
León
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile;
David
D
Necuñir
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile;
Alvaro A
AA
Elorza
Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile;
Soraya E
SE
Gutiérrez
Howard Hughes Medical Institute, Department of Pharmacology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, WA; and.
Randall T
RT
Moon
Fundación Ciencia and Vida, Santiago, Chile.
Alejandra
A
Loyola
Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP) Center for Genome Regulation, Santiago, Chile;
Giancarlo V
GV
De Ferrari
D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin