BCL11 GENES IN NORMAL AND MALIGNANT B CELL DEVELOPMENT

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DESCRIPTION (provided by applicant): Molecular cloning of chromosomal translocations targeted to the immunoglobulin (IG) loci allows the identification of genes of importance in the genesis of normal and malignant B-cells. We have cloned a highly conserved zinc finger gene locus BCL11A, from a chromosomal translocation, t(2;14)(p13;q32.3), that occurs as the sole cytogenetic abnormality in rare and clinically aggressive subset of CLL. All breakpoints involved IG gamma switch regions and clustered 5' of a CpG island associated with BCL11A. BCL11A maps closely telomeric to REL and also appears to be a target gene for amplifications and gains of 2p13 observed frequently in Hodgkin's disease and in extranodal B-NHL. Together the data implicate deregulated expression of BCL1 1A in the pathogenesis of divergent subtypes of aggressive human cancers. There are three common BCL11A isoforms; each is a transcriptional repressor and varies in the number of zinc fingers. BCL11A interacts physically with and shares several similarities with BCL6, a gene frequently translocated to both IG and non-IG associated sites. BCL1 1A shares high identity with a human family member, BCL11B, on chromosome 14q32.1 and with homologues across metazoan evolution. We propose to study the clinical significance of deregulation BCL11 expression in malignancies with abnormalities of chromosome 2p13 and to determine the function of BCL11 in normal and malignant B-cell development Specific approaches include screening for additional (BCL1 1A) and initial (BCL11B) cases containing breaks/amplifications a these loci; functional analysis of transcriptional mechanisms an downstream targets; assessing transforming activities using in vitro and transgenic models; and inactivating the gene by targeted disruption.