Comprehensive genomic screens identify a role for PLZF-RAR alpha as a positive regulator of cell proliferation via direct regulation of c-MYC

K.L. Rice, I. Hormaeche, S. Doulatov, J.M. Flatow, D. Grimwade, Ken Mills, M. Leiva, J. Ablain, C. Ambardekar, M.J. McConnell, J.E. Dick, J.D. Licht

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The t(11; 17)(q23;q21) translocation is associated with a retinoic acid (RA)-insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor alpha (PLZF-RAR alpha) and RAR alpha-PLZF. Using a combination of chromatin immuno-precipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RAR alpha that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RAR alpha as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RAR alpha promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RAR alpha binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RAR alpha may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RAR alpha-transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RAR alpha. (Blood. 2009; 114: 5499-5511)
Original languageEnglish
Pages (from-to)5499-5511
Number of pages13
JournalBlood
Volume114
Issue number27
DOIs
Publication statusPublished - 24 Dec 2009

Bibliographical note

This paper involves the analysis of leukaemia patients with PLZF-RARa gene fusion - this is a rare disease and the paper includes data from 6 patients (representing all the UK patients) - this data was supplied by Mills. This paper continues studies published in 2007 in PNAS (cited 16 times)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

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