Acute promyelocytic leukemia cells (APL; FAB M3) have a specific balanced translocation t(15;17) (q22;12-21) that rearranges the retinoic acid receptor-alpha (RAR-alpha) and the promyelocytic leukemia (PML) genes. Two features distinguish APL from other leukemias. These are: (1) patient-derived APL cells express the normal RAR-alpha and PML alleles and the PML/RAR-alpha that results from the translocation and (2) treatment of APL patients with all-trans retinoic acid (RA) induces complete clinical remissions. Paradoxically, the responses are associated with expression of the aberrant mRNA transcript resulting from this translocation. Two attractive but not mutually exclusive hypotheses exist to explain these clinical responses of RA in APL: the PML/RAR-alpha transcript functions as dominant negative mutation upon normal RAR-alpha function, or it has an inhibitory function upon the PML pathway. This proposal seeks to discriminate between these two possibilities and to better understand the paradoxical response of APL to RA therapy. This will be accomplished through the following specific aims undertaken within the NB4 cell line, the unique cultured ALP cell line aims undertaken within the NB4 cell line, the unique cultured APL cell line containing the t(15;17) and exhibiting a cytodifferentiation response to RA: (1) to select RA-refractory NB4 subclones and correlate resistance with altered structure or expression of PML/RAR-alpha, RAR-alpha and PML, those transcription factors linked to the RA response of APL; (2) to stably transfect the full length RAR-alpha PML, and PML/RAR-alpha cDNAs into NB4 cells and contrast the RA response of these and control cells; (3) to construct recombination plasmids to """"""""knock-out"""""""" the RAR-alpha, PML, and PLM/RAR-alpha alleles and perform homologous recombination in NB4 cells and then assess the RA response of these engineered cells; and (4) to contrast the proliferative and tumorigenic potential of RA treated and untreated parental NB4 cells with its engineered subclones. In this proposal, cellular, biochemical, and molecular genetic techniques are utilized to investigate the mechanism of action of RA, a new anti-cancer agent within a preclinical experimental model of APL. Through the stated aims we hope to better understand the role of the RAR-alpha, PML, and PML/RAR-alpha genes in the RA response of APL.
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