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

• Published in: Blood 2009-12, Vol.114 (27), p.5499
• Main Authors: Rice, Kim L, Hormaeche, Itsaso, Doulatov, Sergei, Flatow, Jared M, Grimwade, David, Mills, Ken I, Leiva, Magdalena, Ablain, Julien, Ambardekar, Charuta, McConnell, Melanie J, Dick, John E, Licht, Jonathan D
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Proliferation; Cell Survival - drug effects; Cell Survival - genetics; Cell Survival - physiology; Chromatin Immunoprecipitation; Cyclin-Dependent Kinase Inhibitor p19 - genetics; Cyclin-Dependent Kinase Inhibitor p19 - metabolism; Dual Specificity Phosphatase 6 - genetics; Dual Specificity Phosphatase 6 - metabolism; Gene Expression Profiling; Gene Expression Regulation, Leukemic - drug effects; Genome, Human - genetics; Genome-Wide Association Study; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; Mice; Oligonucleotide Array Sequence Analysis; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncogene Proteins, Fusion - physiology; Protein Binding; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Tretinoin - pharmacology; U937 Cells; Xenograft Model Antitumor Assays
• ISSN: 1528-0020
• DOI: 10.1182/blood-2009-03-206524

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-RARalpha) and RARalpha-PLZF. Using a combination of chromatin immunoprecipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RARalpha that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RARalpha as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RARalpha promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RARalpha binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RARalpha may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RARalpha-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-RARalpha.