RetinoicAcidReceptorAlphaandPromyelocyticLeukemia.pptVIP

Retinoic Acid Receptor AlphaandAcute Promyelocytic Leukemia Nidhi Thapar April 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) Retinoic Acid Member of a family called retinoids, derived from Vitamin A Enters the nucleus and binds to receptors, initiating transcription factors Signalingby Retinoic Acid RARα normal function In the absence of RA RAR/RXR recruits repression complex Results in transcriptional repression RARα normal function Presence of RA induces the dissociation of repression complex Acetylation of histones leads to promoter clearance which activates transcription Chromosome Translocation Results in PML Translocation occurs between chromosomes 15 and 17 As a result, an abnormal protein product is produced, PML/RARα X- RARα Leads to differentiation blockage Activates target genes leading to overexpression Knock-out Mice RARα-/ RARα- had no effect on phenotype  Triple mutants hard to make Treatment High doses of RA in combination with chemotherapy HDAC inhibitors HDAC inhibitors are therapeutic target Works well in combination with ATRA Potent inducers of growth arrest, differentiation and apoptosis thank you * / / / Lin, et al. Lin, et al. .au / /firsts/mouse.jpegimgrefurl Lin, et al. *