retinoic acid receptor alpha and acute promyelocytic leukemia nidhi thapar april 1, 2004
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Retinoic Acid Receptor Alpha
and
Acute Promyelocytic Leukemia
Nidhi ThaparApril 1, 2004
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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
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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/
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Signalingby Retinoic Acid
http://www.ncbi.nlm.nih.gov/
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RARα normal function
• In the absence of RA RAR/RXR recruits repression complex
• Results in transcriptional repression
Lin, et al.
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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.
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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
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X- RARα
• Leads to differentiation blockage
• Activates target genes leading to overexpression
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http://www.ncbi.nlm.nih.gov/
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Knock-out Mice
• RARα-/ RARα- had no effect on phenotype
• Triple mutants hard to make
http://mbbnet.umn.edu/firsts/mouse.jpeg&imgrefurl
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Treatment
• High doses of RA in combination with chemotherapy
Lin, et al.
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HDAC inhibitors
• HDAC inhibitors are therapeutic target
• Works well in combination with ATRA
• Potent inducers of growth arrest, differentiation and apoptosis
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thank you