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

Retinoic Acid Receptor-Alpha and Its Role in Acute Promyelocytic

Leukemia

By Alex Sheng

What is Retinoic Acid?

The most biologically active retinoid

Derived from Vitamin A

What Does Retinoic Acid Do in the Organism? Regulates neuronal

differentiation. Patterns the

anteroposterior (AP) axes.

Upregulates prepattern and neurogenic genes

Downregulates genes that inhibit neurogenesis.

Effect of RA on the hindbrain

a) Normal CNS

b) Excess RA – missing anterior hindbrain

c) Lower RA – rhombomere changes

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.

RA’s Role in Neurogenesis

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

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.

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.

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.

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.

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

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.

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.

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.

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)

Acute Promyelocytic Leukemia (APL) Often caused by a

chromosomal translocation involving the RARα gene on chromosome 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.

Fusion Proteins PML- RARα and PLZF- RARα

The PML/RARa fusion protein blocks the differentiation of promyelocytes to granulocytes.

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.

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.

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.

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.

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

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