Alternative RUNX1 Promoter Regulation by Wnt/β-Catenin Signaling in Leukemia Cells and Human Hematopoietic Progenitors

• Published in: Journal of cellular physiology Vol. 231; no. 7; pp. 1460 - 1467
• Main Authors: Medina, Matías A., Ugarte, Giorgia D., Vargas, Macarena F., Avila, Miguel E., Necuñir, David, Elorza, Alvaro A., Gutiérrez, Soraya E., De Ferrari, Giancarlo V.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.07.2016
• Subjects: beta Catenin - genetics; Core Binding Factor Alpha 2 Subunit - biosynthesis; Core Binding Factor Alpha 2 Subunit - genetics; Gene Expression Regulation, Developmental; Hematopoiesis - genetics; Hematopoietic Stem Cells - metabolism; Humans; Jurkat Cells; Leukemia - genetics; Leukemia - pathology; Promoter Regions, Genetic; Proto-Oncogene Proteins - genetics; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RUNX1 Translocation Partner 1 Protein; Transcription Factors - genetics; Wnt Signaling Pathway
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.25258

Two distantly located promoter regions regulate the dynamic expression of RUNX genes during development: distal P1 and proximal P2 promoters. We have recently described that β‐catenin increases total Runx1 mRNA levels in human CD34+ hematopoietic progenitors and enhances spatial proximity with its translocation partner ETO. Here, we report that induction of Wnt/β‐catenin signaling in HL60 and Jurkat leukemia‐derived cell lines and CD34+ progenitors selectively activate the production of the longer distal P1‐Runx1 mRNA isoform. Gain‐ and loss‐of‐function experiments revealed that the differential increase in P1‐Runx1 expression is accomplished through a minimal β‐catenin responsive region that includes a highly conserved TCF/LEF‐binding element, located −20/−16 bp upstream of the canonical distal P1‐Runx1 transcription start site. We conclude that the distal P1‐Runx1 promoter is a direct transcriptional target of Wnt/β‐catenin signaling that may be important in normal hematopoiesis or its transition into malignant stem cells during the onset or progression of leukemia. J. Cell. Physiol. 231: 1460–1467, 2016. © 2015 Wiley Periodicals, Inc. We report that induction of Wnt/β‐catenin signaling in leukemia‐derived cell lines and human CD34+ progenitors selectively activate the production of the distal P1‐Runx1 mRNA isoform. We identify a minimal β‐catenin responsive region that includes a highly conserved TCF/LEF‐binding element upstream of the P1‐Runx1 transcription start site. The P1‐Runx1 promoter is a direct transcriptional target of Wnt/β‐catenin signaling, which may be important in normal hematopoiesis or the onset/progression of leukemia.