Acute Promyelocytic Leukemia (APL) is a distinct subtype of acute myeloid leukemia invariably associated with a reciprocal translocation which involves chromosome 17. At the molecular level, the breakpoint on chromosome 17 lies within the RARalpha locus. RARalpha translocates and fuses, in almost all cases, to the PML gene on chromosome 15, and, in few cases, to the PLZF gene on chromosome 11, or the NPM gene on chromosome 5. The current notion is that the PML/ RARalpha, PLZF/ RARalpha and NPM/ RARalpha fusion proteins act in a dominant negative manner to disrupt the normal function of RARalpha and its partners, leading to leukemia. Evidence has accumulated that PML, PLZF and NPM could be invovled in the control of hemopoietic processes and the transduction of mitogenic signals, behaving in this respect as tumor/growth suppressors. They hypothsize that this dual role is disrupted by the dominant negative effect of the fusion protein. They proposed to test the above hypothesis by a direct genetic approacy and on the strength of comparative analysis, with the following specific aims: 1. To define, in knockout mice, the role of PML, PLZF, and NPM in hemopoiesis. They have disrupted the PML gene in mouse ES cells and mice homozygous for the mutation have been generated. PML mutants show a marked reduction of circulating myeloid cells and altered immunological responses. The investigator will investigate hemopoiesis and immunological functions of PML mutant mice. Using a similar approach, he has obtained mice heterozygous for the disruption of the PLZF gene. He will generate mice homozygous for the PLZF mutation and study their hemopoietic processes. Similarly, mice lacking NPM function will be generated and characterized. Differential experimental approaches will be undertaken depending on whether mice lacking PLZF and NPM are viable. 2. To establish, in knockout mice or derived cell lines, PML, PLZF and NPM role in oncogenesis, tumor promotion and tumor progression. He will examine spontaneous or physically/chemically induced tumorigenesis and tumor promotion and progression in PML, PLZF and NPM mutants or in somatic chimeras generated from ES null cells. Furthermore, to determine if loss of these genes cooperates with oncogenes or tumor suppressor genes leading to cancer, he will generate mice lacking either PML, PLZF or NPM and also lacking the p53 tumor suppressor gene, or overexpressing v-Ha-Ras and c-myc, and establish the incidence of spontaneous tumors. In addition, the transforming capacities of v-Ha-Ras or c-myc in cell lines lacking these genes will be defined.