Retinoic Acid Receptor-Alpha and Its Role in Acute Promyelocytic Leukemia

1. Retinoic Acid Receptor-Alpha and Its Role in Acute Promyelocytic Leukemia By Alex Sheng

2. What is Retinoic Acid? • The most biologically active retinoid • Derived from Vitamin A

3. What Does Retinoic Acid Do in the Organism? • Effect of RA on the hindbrain • Normal CNS • Excess RA – missing anterior hindbrain • Lower RA – rhombomere changes • Regulates neuronal differentiation. • Patterns the anteroposterior (AP) axes. • Upregulates prepattern and neurogenic genes • Downregulates genes that inhibit neurogenesis.

4. What Does Retinoic Acid Do in the Organism? • RA controls the number of primary neurons. • In humans, RA also regulates myeloid cell proliferation and differentiation. Primary neurons at the neurula stage.

5. RA’s Role in Neurogenesis

6. The Teratogenic Effect of Retinoic Acid • Retinoic acid is teratogenic in humans at very low doses. • Exposure to RA between 3-5 weeks of pregnancy may result in malformations of the fetus

7. Retinoid Acid Receptor α • Member of the nuclear hormone receptor superfamily that also includes the retinoid X receptor (RXR). • Found in the nucleus of hematopoietic cells.

8. The Normal Function of RAR in the Cell • Receptor for all-trans retinoic acid (ATRA) and 9-cis RA. • Active in cellular differentiation and morphogenesis. • Important for hematopoietic cells differentiation and maturation. • It acts as a tumor suppressor.

9. The Normal Function of RAR in the Cell • In the absence of RA, the RAR/RXR heterodimer recruits a repression complex that causes the deacetylation of core histones resulting in chromatin condensation and transcriptional repression.

10. The Normal Function of RAR in the Cell • In the presence of RA, the repression complex dissociates, promoting the association of coactivator complex that leads to acetylation of core histones, resulting in chromatin relaxation, promotor clearance and transcription activation.

11. RAR Knockouts • Mice selectively deficient in the RAR-alpha 1 isoform appear normal with no discernible disorder in hematopoiesis. • Knockout mice in which both isoforms of RAR have been disrupted display early post natal lethality and testis degeneration, but do not display any overt abnormality in hematopoiesis

12. RAR Knockouts • There are two isoforms of RAR-alpha (RAR-alpha 1 and RAR-alpha 2) • There is genetic redundancy in the RAR-alpha gene.

13. Acute Promyelocytic Leukemia (APL) • A common form of acute myeloid leukemia (AML) • Involves the accumulation of immature promyelocytes in patient bone marrow and peripheral blood.

14. Acute Promyelocytic Leukemia (APL) • ~50 children diagnosed each year. • Represents about one percent of childhood leukemia. • Found more often in children between the ages of two and three, and in adults over 40 • More frequently in children of Hispanic and Mediterranean origin.

15. Symptoms of Acute Promyelocytic Leukemia (APL) • Fatigue • Weakness • Shortness of breath (from anemia) • Easy bruising and bleeding • Fever and infection (from lack of normal white blood cells)

16. Acute Promyelocytic Leukemia (APL) • Often caused by a chromosomal translocation involving the RARα gene on chromosome 17.

17. Fusion Partners of Mutant RARα • promyelocyte gene (PML) • promyelocytic leukemia zinc finger gene (PLZF) • The mutant RARα form fusion proteins PML- RARα and PLZF- RARα.

18. Fusion Proteins PML- RARα and PLZF- RARα • The PML/RARa fusion protein blocks the differentiation of promyelocytes to granulocytes.

19. What Goes Wrong in APL? • PML/RAR alpha fusion protein recruits multiple nuclear co-repressor complex to RAR promoters • This leads to transcriptional repression and promyelocytic differentiation blockage.

20. Treatments for APL • Pharmacological concentrations of RA trigger dissociation of corepressor complexes from PML- RARα but not PLZF- RARα • Also allows for association of coactivator complexes. • Leads to activation of gene expression, leukemia cell differentiation and clinical remission.

22. Treatment Success • Standard frontline therapy for APL has been high doses of all trans RA (ATRA) in combination with chemotherapy. • The treatment results in clinical remission in approximately 90% of patients.

23. Treatments for APL Treatment of ATRA does not kill the undifferentiated promyelocytes. Instead, it allows them to grow and mature normally, to differentiate and to apoptose.

24. Sources • http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemia • Maden, Malcolm. “Retinoid Signaling in the Development of the Central Nervous System." Nature Reviews - Neuroscience 3 (2002): 843-853. • Lin, Richard J et al. “Transcriptional regulation in acute promyelocytic leukemia.” Oncogene (2001) 20, 7204-7215. • Lufkin T. et al. “High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice.” Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7225-9. • Stainier, D.Y.R. and Fishman, M.C. (1992) Patterning the zebrafish heart tube: acquisition of anteroposterior polarity. Dev. Biol. 153: 91-10

25. Make cue cards • Get rid of details and put on cue cards • More pictures – use a mac • Single knockout • Transcription factor • Make a picture for