Staudt's laboratory is currently focused on understanding the molecular pathogenesis of human leukemias and lymphomas caused by nuclear oncogenes. The first area of interest is in diffuse large cell lymphoma caused by the BCL-6 oncogene. BCL-6 encodes a zinc finger protein which has a novel homology domain at its amino terminus, the POZ domain, which is shared by a subset of zinc finger factors. The laboratory has shown that the BCL-6 POZ domain mediates transcriptional repression and homo-dimerization. Expression of BCL-6 mRNA is down-regulated during entry of resting B and T lymphocytes into the cell cycle following a variety of mitogenic stimuli suggesting that the pathogenesis of diffuse large cell lymphoma involves the misexpression of BCL-6 during the cell cycle. A second focus of the lab concerns t(4;11) pre-B cell acute lymphoblastic leukemia caused by a fusion oncogene involving the genes MLL and AF-4. While MLL is a homologue of the Drosophila trithorax gene, AF-4 is not related to previously cloned genes. The lab has cloned a novel lymphoid-restricted homologue of AF-4, termed LAF-4. LAF-4 and AF-4 define a new family of nuclear factors which contain potent transcriptional activation domains. The AF-4 activation domain is included in the MLL-AF-4 fusion protein and thus may contribute to the function of the oncoprotein. The third project relates to t(15;17) acute promyelocytic leukemia caused by a fusion oncogene involving the PML and retinoic acid receptor ` genes. PML has previously been localized to ring-like, sub-nuclear structures termed PODs or ND10s. The lab has cloned a novel lymphoid-restricted gene, LYSP100, which partially co-localizes with PML in novel dot-like, sub-nuclear structures, termed LANDs. By immunoelectronmicroscopy, the LANDs were found to be electron dense, dot-like structures, morphologically distinct from POD/ND10s, that are found in the nucleoplasm, at the nuclear membrane and in the cytoplasm. Thus, PML may function in two morphologically and biochemically distinct sub-nuclear structures.
