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Diffuse Large-Cell Lymphoma MEINRAD BUSSLINGER*, NORMAN Klixt, PETER PFEFFER, PAULA G

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Diffuse Large-Cell Lymphoma MEINRAD BUSSLINGER*, NORMAN Klixt, PETER PFEFFER, PAULA G Proc. Natl. Acad. Sci. USA Vol. 93, pp. 6129-6134, June 1996 Medical Sciences Deregulation of PAX-5 by translocation of the E,t enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma MEINRAD BUSSLINGER*, NORMAN KLIXt, PETER PFEFFER, PAULA G. GRANINGER, AND ZBYNEK KOZMIK Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria Communicated by Max L. Birnstiel, Research Institute of Molecular Pathology, Vienna, Austria, February 22, 1996 (received for review January 26, 1996) ABSTRACT Analyses ofthe human PAX-5 locus and ofthe (KIS-1) that was established from a patient with diffuse 5' region of the mouse Pax-5 gene revealed that transcription large-cell lymphoma (5). Molecular cloning of the KIS-1 from two distinct promoters results in splicing of two alter- translocation breakpoint demonstrated that the IgH locus on native 5' exons to the common coding sequences ofexons 2-10. 14q32 was translocated next to 9pl3 sequences of unknown Transcription from the upstream promoter initiates down- function (5). stream of a TATA box and occurs predominantly in B- We have previously mapped the human PAX-5 gene to lymphocytes, whereas the TATA-less downstream promoter is chromosome 9p13 (6). PAX-5 codes for the transcription factor active in all Pax-5-expressing tissues. The human PAX-5 gene BSAP that is expressed at all stages of B cell development is located on chromosome 9 in region p13, which is involved except in terminally differentiated plasma cells and that is in t(9;14)(p13;q32) translocations recurring in small lympho- known to regulate the CD19 gene as well as the Is promoter cytic lymphomas of the plasmacytoid subtype and in derived and 3'a enhancer of the IgH locus (for review, see ref. 7). In large-cell lymphomas. A previous molecular analysis of a addition to all B-lymphoid tissues, the Pax-5 gene is also t(9;14) breakpoint from a diffuse large-cell lymphoma (KIS-1) expressed in the embryonic midbrain and adult testis of the demonstrated that the immunoglobulin heavy-chain (IgH) mouse (8). Consistent with this expression pattern, gene locus on 14q32 wasjuxtaposed to chromosome 9pl3 sequences inactivation in the mouse germ line demonstrated that Pax-5 of unknown function [Ohno, H., Furukawa, T., Fukuhara, S., plays an essential role in B-lymphopoiesis and midbrain de- Zong, S. Q., Kamesaki, H., Shows, T. B., Le Beau, M. M., velopment (9). McKeithan, T. W., Kawakami, T. & Honjo, T. (1990) Proc. Here we report the cloning and characterization of the Natl. Acad. Sci. USA 87, 628-632]. Here we show that the KIS-1 entire human PAX-5 locus and of the 5' region of the mouse translocation breakpoint is located 1807 base pairs upstream Pax-5 gene, indicating that both genes are transcribed from two of exon 1A ofPAX-5, thus bringing the potent E,i enhancer of distinct promoters that are differentially regulated during the IgH gene into close proximity of the PAX-5 promoters. development. Southern blot analysis and direct sequence These data suggest that deregulation ofPAX-5 gene transcrip- comparison mapped the KIS-1 translocation breakpoint 1807 tion by the t(9;14)(p13;q32) translocation contributes to the base pairs upstream of exon 1A of PAX-5. As a consequence, pathogenesis of small lymphocytic lymphomas with plasma- the IgH and PAX-5 genes are arranged in a head-to-head cytoid differentiation. configuration, resulting in the juxtaposition of the potent E,L enhancer next to thePAX-5 promoters. These data suggest that Hematologic malignancies are often associated with specific deregulation of PAX-5 transcription through enhancer inser- chromosomal translocations that result in the oncogenic con- tion by the t(9;14)(p13;q32) translocation contributes to the version of regulatory genes controlling differentiation, prolif- pathogenesis of small lymphocytic lymphoma with plasmacy- eration, or cell survival. In B cell neoplasms, chromosomal toid differentiation. translocations frequently involve the immunoglobulin heavy- chain (IgH) gene locus on chromosome 14q32. Molecular MATERIALS AND METHODS studies of these abnormalities have led to the isolation of novel oncogenes located at the translocation breakpoint and pro- Oligonucleotides. The following oligonucleotides were used vided insight into their role in lymphomagenesis. Prominent in this study: 1, 5'-GATCATGTCCTGTTCTCGCCAACAT- examples are the c-myc gene (8q24) implicated in Burkitt CACAAGATGT-3'; 2, 5'-CGGCTGCAGAGGTGTTTTCT- lymphoma, the bcl-1 gene (11q13) involved in mantle cell GATCT-3'; 3, 5'-TTGAGGCACTGCAGCA(T)17-3'; 4, 5'- lymphoma, the bcl-2 gene (18q21) activated in follicular lym- TTGAGGCACTGCAGCA-3'; 5, 5'-TCCTTTGGCGGACT- phoma, and the bcl-6 gene (3q27) implicated in diffuse large- ACATCTGG-3'; 6, 5'-GCGGGATCCTGTCCTGATGGTC- cell lymphoma (for reviews, see refs. 1 and 2). 3'; 7, 5'-AGCAAGTTCAGCCTGGTTAAGTCC-3'; 8, 5'- A new recurring translocation, t(9;14)(p13;q32), has cyto- GCCAAGCTTCCCCAAGCTGATTCACTCCTCC-3' genetically been identified in 52% of non-Hodgkin lympho- Subcloning and DNA Sequencing of PAX-5 Cosmid, Yeast mas (3). This characteristic translocation is highly correlated Artificial Chromosome (YAC), and P1 Clones. The isolation of with small lymphocytic lymphomas of the plasmacytoid sub- mouse and human PAX-5 cosmids has been described (6, 9). A type (3) that are referred to as lymphoplasmacytoid immuno- 2.2-kb EcoRI, a 7.2-kb SacI, and a 3-kb HindIII fragment were cytomas in the Kiel classification (4). This B cell neoplasm is subcloned from cos-mPax5-14 into pSP64 or pBluescript initially of low grade, but may slowly progress toward trans- (Stratagene) to generate p5.14-E2.2, p5.14-S7.2, and p5.14- formation into a more aggressive large-cell lymphoma (3). The same t(9;14) translocation has been identified in a cell line Abbreviation: YAC, yeast artificial chromosome. Data deposition: The sequences reported in this paper have been deposited in the GenBank data base (accession nos. U56835-U56838). The publication costs of this article were defrayed in part by page charge *To whom reprint requests should be addressed. payment. This article must therefore be hereby marked "advertisement" in tPresent address: Medical Research Council Laboratory of Molecular accordance with 18 U.S.C. §1734 solely to indicate this fact. Biology, Hills Road, Cambridge CB2 2QH, England. 6129 Downloaded by guest on September 27, 2021 6130 Medical Sciences: Busslinger et al. Proc. Natl. Acad. Sci. USA 93 (1996) H3.0. The probes p5.1-E3.0 and p5.3-E3.6 were obtained by probes pSP6-ExlA and pSP6-ExlA/2 were generated by clon- subcloning a 3-kb EcoRI fragment from cos-hPAX5-1 and a ing a 1038-bp TaqI fragment from p5.14-E2.2 and a 261-bp 3.6-kb EcoRI fragment from cos-hPAX5-3, respectively. A TaqI-BamHI fragment from mBSAP-1 cDNA (8) into theAccI 8.7-kb BamHI, a 1.8-kb PstI, and a 2.3-kb NheI fragment were site of pSP64, respectively. A 220-bp cDNA fragment was subcloned from the YAC 37G-D10 into pSP64 to generate amplified by reverse transcription-PCR with primers 2 and 8 pD10-B8.7, pD10-P1.8, and pD10-N2.3, respectively. All sub- from RNA of mouse embryos at day 12.5 and cloned into cloned DNA fragments were sequenced on an automated pSP64 to generate the probe pSP6-ExlB/2. sequencer (Applied Biosystems) by primer walking. 5' End Determination of PAX-5 Transcripts. A 274-bp Determination of the Exon-Intron Structure of the PAX-5 Sau3AI-SmaI fragment isolated from clone pD10-B8.7 was 5' Gene. The junctional sequences of exons 2-6 and 9-10 were end-labeled at the Sau3AI site in exon 1A and used for S1 directly determined on cos-hPAX5-1, -2 and -3 with exon- nuclease analysis as described (14). For primer extension assay, specific primers. Exon 7 was subcloned as a 4.5-kb EcoRI the 5' end-labeled oligonucleotide 1 was hybridized with 5 tug fragment from YAC 16D9 and exon 8 as a 3.4-kb PstI fragment of poly(A)+ RNA from BJA-B and RPMI 8226 cells followed from P1 clone 355 before DNA sequencing. by reverse transcription as described (15). Isolation and Characterization of PAX-5 YAC and P1 Clones. A human YAC library, cloned in pYAC4 (10) and RESULTS obtained from the Human Genome Mapping Project Resource Centre (Harrow, U.K.), was screened with the labeled EcoRI Cloning and Characterization of the Human PAX-5 Locus. inserts of p5.1-E3.0 and p5.3-E3.6, resulting in the isolation of Eight different cosmids containing PAX-5 coding sequences YAC 37G-D10. A second YAC, 16D9, cloned in pJS97 and were previously isolated (6), and individual exons were as- pJS98 and isolated from a flow-sorted chromosome 9 library signed to these clones by direct DNA sequencing. The map of (11), was kindly provided to us by M. K. McCormick (Mas- three representative cosmids that cover 100 kb of the PAX-5 sachusetts General Hospital, Harvard Medical School, Bos- gene is shown in Fig. 1. To clone the missing 5' region as well ton). A human P1 library, generated in pADlOsacBII (12) and as exons 7 and 8, we next screened human YAC and P1 libraries distributed by the Imperial Cancer Research Fund Reference (10, 16) with two unique DNA probes originating from the 5' Library Database (London), was screened with the same DNA and 3' regions of the PAX-5 locus (p5.1-E3.0 and p5.3-E3.6). probes, resulting in the identification of clone ICRFP700H0355 The YAC clone 37G-D10 and P1 clone 355 were identified in (abbreviated as P1 355).
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