NOVEL GENE REARRANGED WITH BAR-ALPHA LOCUS IN CANCER

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Recently the etiology of a number of human cancers has been associated with chromosomal translocations leading to the formation of novel fusion proteins. Amongst these fusions are chimeric transcriptional regulators. Recently, the fusion between the PML gene and the RARalpha gene was found to be the result of the t(15; 17) associated with acute promyelocytic leukemia (APL). The PML-RAR fusion protein has different transcriptional effects compared to RARalpha and its transcriptional effect compared to the wild-type PML protein remains incompletely characterized. It is currently believed that an understanding of the functions of the wild-type and fusion PML proteins may yield new insights into the etiology of APL. In a search for novel rearrangements of the RARalpha in patients with APL we have isolated a new gene translocated to the RARalpha locus in a patients with APL and a t(11; 17). The novel gene encodes a protein containing 9 zinc fingers domains and places the protein in a large family of transcriptional regulators related to the Drosophila protein Kruppel as well as a large number of human transcription factors including the WT-1 tumor suppressor protein. In contrast to PML, which is expressed in all hematopoietic lineages examined, the novel gene, we have termed PLZF (Promyelocytic Leukemia Zinc Finger), is expressed predominantly in the myeloid lineage. PLZF is expressed in a stage specific manner, down regulated in myeloid cell lines in response to retinoic acid, present in bone marrow myeloid precursors but absent in peripheral blood granulocytes. In this proposal we will complete the cloning of the PLZF gene and the fusion cDNAs linking PLZF and the RARalpha. With these reagents in hand we further our studies into the pattern of expression of the PLZF gene and protein in normal hematopoiesis and in acute leukemia. We will isolate the genomic fragment containing the cis-acting elements involved in the control of PLZF expression. We will determine the DNA binding and transcriptional effector activity of the PLZF protein and search for genes which may be the target of the PLZF protein. We will compare and contrast the transcriptional and DNA binding activity of the wild-type PLZF protein and PLZF-RARalpha fusion proteins, in order to determine what role they may have had in the etiology of our index patient's disease. We will determine whether other patients with APL or other forms of acute myeloid leukemia have PLZF/RAR abnormalities. Collectively these studies will yield new insight into a myeloid lineage specific gene, its role in normal granulocytopoiesis and possible role in the etiology of acute leukemia. At the same time we will learn more of the role of retinoic acid and its receptor in the pathology and treatment of leukemia.