SMALL DELETIONS OCCUR IN HIGHLY CONSERVED REGIONS OF THE LAZ3 BCL6 MAJOR TRANSLOCATION CLUSTER IN ONE CASE OF NON-HODGKINS-LYMPHOMA WITHOUT3Q27 TRANSLOCATION/

The LAZ3/BCL6 gene encoding a Zinc-finger nuclear protein is altered i n Non-Hodgkin's Lymphomas (NHLs) by translocations, mutations and/or d eletions clustered in its 5' non coding region, in a 3.3 Kbp EcoRI fra gment which thus defines the Major Translocation Cluster (MTC). In the present study, we describe at the molecular level the deletions found in the MTC of two (NHL) cases using, (i) DNA obtained from a patient (GUI) with a monosomy 3 and three microdeletions of 101, 22, 25 bp in its unique untranslocated 3q27 allele; (ii) a cell line derived from a patient (VAL) carrying a t(3;4) (q27;pll) translocation and a 2.4 Kbp deletion in the untranslocated allele. As the MTC is recurrently subj ect to alterations, me have cloned and sequenced the murine equivalent of the human MTC and promoter region in an attempt to identify sequen ces well conserved in mammals that may be thus important for the LAZ3/ BCL6 gene regulation. We show that the human and mouse 5' upstream reg ions of the LAZ3/BCL6 gene although mainly intronic share a particular ly high homology of 79% on the overall sequence. Strikingly, the small sequences which are deleted in patient (GUI) are highly conserved (81 %, 100% and 92% respectively). Furthermore, they may play a role in th e pathogenesis since proteins prepared from B cell lines and HeLa nucl ear extracts bind to these sequences in gel retardation assays. Althou gh a large part of this region is intronic, the high conservation of i ts sequence and the frequency of alterations in NHLs suggest that they are likely to be significant for the regulation of the LAZ3/BCL6 gene .