Abstracts 139

39 Deletion of 9p in ALL

M Diaz

This abstract was unavailable at the time of printing.

41 STRUCI-URAL ALTERATIONS OF THE BCL-6 GENE IN B CELL LYMPHOMA. R. Dalla-Favera’. B.H. Ye’. A. Migliazza’. S.R. Chaganti*. W. Changz.

C-C. Chang’. J. Zhang’, G. Cattoretti’. H. Niul, K. Offit:, R.S.K. Chaganriz. *Department of Pathology, Columbia University, New York, NY 10032; *Cell Biology and Generics Program, Memorial Sloan-Kettenng Cancer Center. New York. NY 10021.

A substantial fraction (30-40%) of diffuse large-cell iymphoma (DLCL), the most frequent and clinicallv relevant type of non-Hodgkin lymphoma (NHL). is assoc(aated with rearrangements of the BCL-6 gene (Ye. BH et al.. Science 262:747. 1993; Lo Coca, F er al., Blood 83:1757. 1994) These lesions have clinical significance Smce they identify a subset of DLCL characterized by extranodal origin and favorable prognosis (Offit, K et al.. New Engl. 1. Med. 331, 74, 1994. The BCL-6 gene encodes a 9.5 kD nuclear phosphoproteln preferentially expressed in mature B-cells and down-regulated during plasmacell differentiation. Ttns proreIn contains SIX C- terminal QH2-1ype zmc-fingers and a N-termmal ZIN/POZ domain, a putative protein-protein interaction domain common to a subset of zinc-finger proteins includmg several Drosophila developmental regulators. BCL-6 binds IO specific DNA sequences through Ifs zmc fingers and contams a potent transcriprional repressor domain suggesting that it may funcnon as a uanscnption factor. As a consequence of rearrangements affecting band 3q27, the BCL-6 promoter region is truncated and the coding domain is linked downstream fo heterologous promoters uanslocared from other chromosomes. In ad&non to chromosomal rearrangements, a recent study revealed the presence of somatic mutations within a 4 kb region spanmng the BCL-6 first non-coding exon in 14 of 18 DLCL cases (78%) carrymg unrearranged BCL-6 genes. but not in 190 other biopsies including most types of solid tumors. Thus. considering both rearrangements and mutations, >80% of DLCL carry alterations in the 5’ non coding region of BCL-6 The frequency, clustering, and disease-assocration. of rhese alterations suggest that they may contribute to lymphomagenesis, presumably by altering BCL-6 gene expressIon.

40 CHROMOSOME TRANSLOCATIONS IN 1 CELL ACUTE LEUKEMIA. Robert Bash, lsobel Wadman and Richard Baer. UT Southwestern Medical Center, Dallas. Texas.

Cytogenetlc studies have identified several tumor- specific chromosome translocations in children with T cell acute lymphoblastic leukemia (T-ALL). Individually, each of these translocations is found in a relatively small proportion of the T-ALL patient population (~10%). Nevertheless. each has been implicated as a contributing factor in leukemogenesis on the basis of its recurrence In unrelated patients and its unique assoclatlon with T-ALL. These translocations serve to cal;gnant:j activate protc-oncogenes by transposing them into the T cell receptor genes on chromosomes 7 or 14. To date, eight distinct genes have been shown to be activated by this mechanism in T-ALL patients. The protein products of these genes Include two families of presumptive transcription factors. m, m, and Lyle encode a unique subgroup of basic helix-loop-helix (bHLH) proteins that share exceptional homology in their bHLH sequences. TTGl/RBTNl and m encode highly -- related proteins that possess cysteine-rich LIM motifs. We recently found that TTGl/RBTNl and RBTNZ polypeptides have the ability to interact with each of the leukemogenic bHLH proteins (TALl, TALL. and LYLl). These interactions occur in viva, and they are mediated by sequences within the LIM and bHLH domains. The LIMjbHLH interactions are highly specific in that lTGl/RBTNl and RBTN2 will associate with TALl, TAL2, and LYLI, but not with other bHLH proteins. Finally, we have identified a subset of leukemia patients that harbor tumor-specific rearrangements of both their m and m genes. Thus, the activated alleles of these genes may promote ieukemia cooperatively, perhaps as a result of bHLH/LIM interactions between their protein oroducts.