Acute Promyclocytic Leukemic is a distinct subtype of acturte myeloid leukemia associated with a reciprocal translocation which always involves chromosome 17 ana variably involves chromosomes 15, 11 or 5. At the molecular levekm tge breakpoints lie within the RARalpha locus on chromosomes 17, the PNL gave on 15, the PLZF gene on 11 and the NFM gene on chromosome 5. The investigator hypothesizes that the PML/RARalpha, PLZF/RARalpha and NFM/RARalpha fusion proteins act in a dominant negative manner the distruct the normal function of RARalpha/PLZF as well as aberrant P products cooperate synergistically leading to leukemia. He proposes to test the above hypothesis in vivo by a direct genetic approach with the following Specific Aims: 1) To define the leukemogenic role of individual APL specifi fusion proteins by generating transgenic mice in which the expression of these molecules is restricted to the hemopoietic/myeloid cellular compartment. Hemopoiesis of the transgenes will be analyzed to disclose the leukemogenic potential of the infividual fusion molecules. In addition, the various transgenes will be intercrossed to reproduce in vivo the genetic complexity observed in the APL blast, and to elucidate the possible cooperative roles of these molecules in the full blown leukemia. 2) To establish the role of PML, PLZF, NPM and RARalpha in APL promotion and progression. To this end, he will interbreed the various transgenes with their respective knockout mice in order to generate transgenes for the fusion molecules in a PML, PLZF and RARalpha +/- and -/- genetic background, and will interbreed the various knockout mice with each other. Hemopoiesis and leukemogenesis in the resulting transgene combinaiton will be analyzed on a comparative basis. p
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