Retinoic Acid Receptor Alpha and Acute Promyelocytic Leukemia

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Retinoic Acid Receptor AlphaandAcute
Promyelocytic Leukemia

• Nidhi Thapar
• April 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//www.cancer.gov
http//my.webmd.com/
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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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RARa normal function

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

Lin, et al.
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RARa 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/RARa

http//www.genetics.com.au
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X- RARa

• 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

• RARa-/ RARa- had no effect on phenotype
• Triple mutants hard to make

http//mbbnet.umn.edu/firsts/mouse.jpegimgrefurl
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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