Final Report Summary - APL (ANALYSIS OF PML/RARA ONCOGENIC COMPLEX IN ACUTE PROMYELOCYTIC LEUKEMIA) Acute promyelocytic leukemia (APL) represents 10% to 15% of acute myeloid leukemias in adults. It is caused by a variety of chromosomal translocations into the retinoic acid receptor-α (RARα) gene. The t(15;17)(q22;q11.2) is the most common translocation and gives rise to promyelocytic leukemia PML- RARα fusion protein. PML-RARα is a transcriptional repressor that associates with a corepressor complex leading to transcriptional repression and thus, promyelocytic differentiation blockage. All-trans retinoic acid (RA), a derivative of vitamin A and the physiologic ligand of RARα, is able to elicit complete remission of APL and has been successfully used in clinical treatment of APL. Pharmacologic concentrations of RA trigger the dissociation of the correpressor complex and the recruitment of the coactivator complex, and lead to changes in gene expression, APL cell differentiation, but also degrade the fusion via proteasome by the retinoic acid‐bound RARα moiety of PML-RARα. It has been suggested that while transcriptional activation control differentiation, this may not be the primary basis for the therapeutic efficacy of RA in clearing APL-associated t(15;17). Indeed, only the leukemia initiating cells (LICs) clearance is responsible for the remission of mouse APL and high concentrations of RA are required for complete PML-RARα catabolism and full LIC clearance. Related documents final1-apl-publishable-summary.pdf
