Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC.
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.
Division of Hematology/Oncology, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA.
Kim L
KL
Rice
Itsaso
I
Hormaeche
Sergei
S
Doulatov
Jared M
JM
Flatow
David
D
Grimwade
Ken I
KI
Mills
Magdalena
M
Leiva
Julien
J
Ablain
Charuta
C
Ambardekar
Melanie J
MJ
McConnell
John E
JE
Dick
Jonathan D
JD
Licht
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; C492209:PLZF-RARalpha fusion protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014212:Tretinoin; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse