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Altered retinoic acid receptors
1CNRS UPR 9051, Paris, France.
Summary
Altered retinoic acid receptors are linked to rare cancers. In acute promyelocytic leukemia (APL), the PML/RARalpha fusion gene drives cancer, but retinoic acid therapy targets this genetic defect for remission.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Altered retinoic acid receptors (RARs) are implicated in human neoplasms like hepatocellular carcinoma and acute promyelocytic leukemia (APL).
- RARbeta rearrangements are specific to hepatocellular carcinoma, while APL characteristically involves RARalpha fusion with the PML gene via t(15;17) translocation.
- APL serves as a crucial model in cancer biology due to successful differentiation therapy.
Purpose of the Study:
- To discuss the molecular mechanisms underlying PML/RARalpha fusion leukemogenesis in APL.
- To explore the role of dominant-negative inhibition in nuclear receptor and PML functions in cancer development.
- To highlight the significance of retinoic acid in APL treatment and cancer therapy.
Main Methods:
- Review of existing literature on retinoic acid receptors and human neoplasms.
- Analysis of the molecular basis of t(15;17) translocation in APL.
- Discussion of dominant-negative inhibition mechanisms.
Main Results:
- The PML/RARalpha fusion protein is a general feature of APL, resulting from the t(15;17) translocation.
- Retinoic acid induces complete remissions in APL, demonstrating effective differentiation therapy.
- The molecular basis involves dominant-negative inhibition of nuclear receptor and PML functions.
Conclusions:
- Targeting the PML/RARalpha genetic lesion with retinoic acid represents a breakthrough in cancer therapy.
- Understanding the molecular pathogenesis of APL provides insights into nuclear receptor function and oncogenesis.
- APL exemplifies successful targeted therapy and differentiation induction in malignancy.