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

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.