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Abstract:
Nuclear receptors comprise a large family of ligand-dependent transcription factors that display considerable specificity in and selectivity in regulating the genetic programs they ultimately influence. The response to retinoic acid (RA) is mediated by two families of transcription factors which include the retinoic acids receptors (RARs) and the retinoid X receptors (RXRs). In human acute promyelocytic leukemia (APL), RAR alpha becomes an activated oncogene as a consequence of its fusion to the PML locus. Because patients with APL can be induced into remission with high dose RA therapy, we propose that PML-RAR is a new class of dominant negative oncogene that disrupts a structure that includes at least five other proteins. This mega-complex, referred to as a "POD", is disrupted in leukemic cells expressing the oncoprotein and is reassembled following high dose RA therapy in both cell culture an in patients.
Insights
High-dose retinoic acid (RA) therapy can induce remission in acute promyelocytic leukemia (APL) by reassembling a disrupted protein complex. This suggests PML-RAR oncogene disrupts a crucial cellular structure in APL.
Area of Science:
- Molecular biology
- Cellular biology
- Oncology
Background:
- Nuclear receptors are ligand-dependent transcription factors regulating gene expression.
- Retinoic acid (RA) response involves retinoic acid receptors (RARs) and retinoid X receptors (RXRs).
- Acute promyelocytic leukemia (APL) involves the PML-RAR alpha oncogene.
Purpose of the Study:
- To investigate the role of the PML-RAR oncogene in APL pathogenesis.
- To understand the mechanism by which RA therapy induces remission in APL.
- To characterize the protein complex disrupted by PML-RAR.
Main Methods:
- Analysis of the PML-RAR oncogene in APL.
- Investigation of RA signaling pathways.
- Identification and characterization of protein-protein interactions within the "POD" complex.
Main Results:
- PML-RAR acts as a dominant-negative oncogene, disrupting a multi-protein complex called "POD".
- This "POD" complex is disrupted in leukemic cells expressing PML-RAR.
- High-dose RA therapy reassembles the "POD" complex in APL cells and patients.
Conclusions:
- PML-RAR oncogene disrupts a critical "POD" mega-complex in APL.
- Reassembly of the "POD" complex by RA therapy is a key mechanism for inducing remission in APL.
- PML-RAR represents a novel class of dominant-negative oncogene.