PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia

Kankan Wang, Ping Wang, Jiantao Shi, Xuehua Zhu, Miaomiao He, Xiaohong Jia, Xianwen Yang, Fei Qiu, Wen Jin, Maoxiang Qian, Hai Fang, Jianqing Mi, Xuzhi Yang, Huasheng Xiao, Mark Minden, Yanzhi Du, Zhu Chen, Ji Zhang

Research output: Contribution to journalArticle (Academic Journal)

116 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)186-97
Number of pages12
JournalCancer Cell
Volume17
Issue number2
DOIs
Publication statusPublished - 17 Feb 2010

Bibliographical note

2010 Elsevier Inc. All rights reserved.

Keywords

  • Humans
  • 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
  • Trans-Activators
  • Cell Line
  • Oncogene Proteins, Fusion

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