PML/RARalpha is of crucial importance in acute promyelocytic leukemia (APL) both pathologically and therapeutically. Using a genome-wide approach, we identified in vivo PML/RARalpha binding sites in a PML/RARalpha-inducible cell model. Of the 2979 targeted regions, >62% contained canonical PU.1 motifs and >84% of these PU.1 motifs coexisted with one or more RARE half (RAREh) sites in nearby regions. Promoters with such PU.1-RAREh binding sites were transactivated by PU.1. PU.1-mediated transactivation was repressed by PML/RARalpha and restored by the addition of all-trans retinoic acid (ATRA). Genes containing such promoters were significantly represented by genes transcriptionally suppressed in APL and/or reactivated upon treatment with ATRA. Thus, selective targeting of PU.1-regulated genes by PML/RARalpha is a critical mechanism for the pathogenesis of APL.
2010 Elsevier Inc. All rights reserved.
- Gene Expression Regulation, Leukemic
- Binding Sites
- Base Sequence
- Promoter Regions, Genetic
- Proto-Oncogene Proteins
- Chromatin Immunoprecipitation
- Leukemia, Promyelocytic, Acute
- Molecular Sequence Data
- Myeloid Cells
- Consensus Sequence
- Cell Line
- Oncogene Proteins, Fusion