retinoic acid receptor alpha and acute promyelocytic leukemia

Retinoic Acid Receptor Alpha

and

Acute Promyelocytic Leukemia

Nidhi ThaparApril 1, 2004

Acute Promyelocytic Leukemia

• Proliferation of immature blood cells

• 10,600 new cases of AML each year.

• Most patients with APL achieve a complete remission when treated (with ATRA)

http://my.webmd.com/http://www.cancer.gov

Retinoic Acid

• Member of a family called retinoids, derived from Vitamin A

• Enters the nucleus and binds to receptors, initiating transcription factors

http://www.ncbi.nlm.nih.gov/

Signalingby Retinoic Acid

http://www.ncbi.nlm.nih.gov/

RARα normal function

• In the absence of RA RAR/RXR recruits repression complex

• Results in transcriptional repression

Lin, et al.

RARα normal function

• Presence of RA induces the dissociation of repression complex

• Acetylation of histones leads to promoter clearance which activates transcription

Lin, et al.

Chromosome Translocation Results in

PML• Translocation occurs between

chromosomes 15 and 17• As a result, an abnormal protein

product is produced, PML/RARα

http://www.genetics.com.au

X- RARα

• Leads to differentiation blockage

• Activates target genes leading to overexpression

http://www.ncbi.nlm.nih.gov/

Knock-out Mice

• RARα-/ RARα- had no effect on phenotype

• Triple mutants hard to make

http://mbbnet.umn.edu/firsts/mouse.jpeg&imgrefurl

Treatment

• High doses of RA in combination with chemotherapy

Lin, et al.

HDAC inhibitors

• HDAC inhibitors are therapeutic target

• Works well in combination with ATRA

• Potent inducers of growth arrest, differentiation and apoptosis

thank you