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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2683-2690
The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR
interacts with co-repressor and co-activator proteins and exhibits both
positive and negative transcriptional properties
Robert L. Redner,
J. Don Chen,
Elizabeth A. Rush,
Hui Li, and
Sheri L. Pollock
From the Division of Hematology/Oncology, Department of Medicine,
University of Pittsburgh Medical Center, and the University of
Pittsburgh Cancer Institute, Pittsburgh Pennsylvania; and the
Department of Pharmacology and Molecular Toxicology, University of
Massachusetts Medical School, Worcester, Massachusetts.
The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the
genes for nucleophosmin (NPM) and the retinoic acid receptor alpha
(RAR ). Two NPM-RAR molecules are expressed as a result of
alternative RNA splicing. Both contain RAR sequences that encode the
DNA binding, heterodimerization, and ligand activation domains of
RAR. This study was designed to test the ability of these fusion
proteins to act as transcriptional activators of retinoic acid
responsive promoters. The NPM-RAR fusion proteins bind to retinoic acid
response element sequences as either homodimers or as heterodimers with
RXR. Transcription of retinoic acid-inducible promoters is activated
by the fusion proteins in the presence of retinoic acid. The level of
transactivation induced by the NPM-RAR fusions differs from the level
of transactivation induced by wild-type RAR in both a promoter and
cell specific fashion, and more closely parallels the pattern of
activation of the PML-RAR fusion than wild-type RAR. In addition,
NPM-RAR decreases basal transcription from some promoters and acts in a
dominant-negative fashion when co-transfected with wild-type RAR.
Both NPM-RAR and PML-RAR interact with the co-repressor protein SMRTe
in a manner that is less sensitive than RAR to dissociation by
retinoic acid. Retinoic acid induces binding of the co-activator
protein RAC3. These data indicate that the NPM-RAR fusion proteins can modulate expression of retinoid-responsive genes in a positive or
negative manner, depending on context of the promoter, and lend support
to the hypothesis that aberrant transcriptional activation underlies
the APL phenotype.
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