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Retinoic Acid Receptor Alpha (RARα)

Retinoic Acid Receptor Alpha (RARα). Acute Promyelocytic Leukemia (APL). APL Overview. Subtype of AML (5-8% of AML adults) Abnormal accumulation of promyelocytes resulting in decreased production of RBCs Median age is 40 years Increased incidence in patients from Latin America

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Retinoic Acid Receptor Alpha (RARα)

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  1. Retinoic Acid Receptor Alpha(RARα) Acute Promyelocytic Leukemia (APL)

  2. APL Overview • Subtype of AML (5-8% of AML adults) • Abnormal accumulation of promyelocytes resulting in decreased production of RBCs • Median age is 40 years • Increased incidence in patients from Latin America • Anemia and thrombocytopenia

  3. RARα is a transcription factor • Nuclear receptor • Ligand-inducible transcriptional regulator • Ligand is retinoic acid (RA) RARα Cyberlipid Center; www.cyberlipid.org

  4. Active transcription factor is a heterodimer • RARα forms heterodimer with RXRs • Heterodimer binds DNA sequence called RA-response element (RARE) Marlétaz F, et al. Int J Biol Sci 2006; 2:38-47.

  5. Retinoic Acid Absent • RAR-RXR heterodimer is a repressor • Co-repressors modify histones • SMRT, N-CoR • mSin3 • HDACs Marlétaz F, et al. Int J Biol Sci 2006; 2:38-47.

  6. Retinoic Acid Present • Repression complex dissociates and a co-activator complex assembles • Co-activator complex modifies histones to induce transcriptional activation Marlétaz F, et al. Int J Biol Sci 2006; 2:38-47.

  7. Homologous recombination Disrupt exon 8, which prevents synthesis of all RARα isoforms Scientists knocked outRARα Gene in Mice Lufkin, Thomas, et al. Proc. Natl. Acad. Sci. USA. Vol. 90, pp. 7225-7229

  8. RARα-null mutants viable but generally die before 2 months • Intercross RARα heterozygotes to give RARα-null homozygotes • RARα gene disruption is not embryonic lethal • RARα, RARβ and RARγ are highly redundant Lufkin, Thomas, et al. Proc. Natl. Acad. Sci. USA. Vol. 90, pp. 7225-7229

  9. Testis Degeneration in RARα Mutant Mice • Male RARα-null homozygotes that survived for > 2 months were sterile • Severe degeneration of germinal epithelium in testes Lufkin, Thomas, et al. Proc. Natl. Acad. Sci. USA. Vol. 90, pp. 7225-7229

  10. Chromosomal Translocation causes mutation • Chromosome 17 • Fusion proteins created with 5 common partners • PML • PLZF • NPM • NuMA • Stat5b Medicine OnLine. www.meds.com

  11. Fusion proteins can form homodimers • Homodimer associates with multiple units of the co-repressor complex • Enhanced transcriptional repression Lin, Richard, et. al. “Transcriptional regulation in APL”

  12. Fusion proteins react strongly with co-repressors to recruit HDACs • Physiological [RA] will not dissociate repression complex Lin, Richard, et. al. “Transcriptional regulation in APL”

  13. High [RA] dissociates repression complex formed by some fusion proteins • PML-RARα but not PLZF-RARα Lin, Richard, et. al. “Transcriptional regulation in APL”

  14. Target genes involved in myeloid proliferation and differentiation • p21WAF, C/EBP, HoxA1, etc. • Inhibition blocks differentiation Lin, Richard, et. al. “Transcriptional regulation in APL”

  15. Treatment • Pharmacological [RA] with chemotherapy • Possibly HDAC inhibitors Lin, Richard, et. al. “Transcriptional regulation in APL”

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