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Novel Genomic Imbalances and Chromosome Translocations Involving C-Myc Gene in Burkitt’S Lymphoma DB Zimonjic, C Keck-Waggoner and NC Popescu

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Novel Genomic Imbalances and Chromosome Translocations Involving C-Myc Gene in Burkitt’S Lymphoma DB Zimonjic, C Keck-Waggoner and NC Popescu Leukemia (2001) 15, 1582–1588 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu Novel genomic imbalances and chromosome translocations involving c-myc gene in Burkitt’s lymphoma DB Zimonjic, C Keck-Waggoner and NC Popescu Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, MD, USA In this study, CA46 and ST486, two Epstein–Barr (EBV) nega- involving the c-myc locus on chromosome 8q24 to any of tive cell lines derived from sporadic BL, were analyzed by multi- the three immunoglobulin genes loci on chromosomes 14q32, color spectral karyotyping, G-banding, fluorescence in situ 8 hybridization with single-copy gene probes, and comparative 2p11 or 22q11. Although all the translocations result in c- genomic hybridization (CGH). In addition to reciprocal myc gene deregulation, the position of the breakpoints may t(8;14)(q24;q32) translocation involving c-myc and IgH loci, we varyfrom case to case. The breakpoint in most common trans- identified a t(7;8;14)(q11.2;q24;q32) translocation in CA 46 cells location t(8;14) cluster within or near myc locus.9 In two BL and t(8;14;18)(q24;q32;q23) in ST486 cells. Both rearrange- cell lines, CA46 and ST486, the breakpoints involve an almost ments were not previously described in BL and resulted in identical site within the first intron of c-myc.10 In both lines, transposition of myc sequences in a new genomic configur- ation. Several DNA imbalances mapped by CGH at the same the first noncoding exon of the gene is retained on chromo- sites in both lines, may reflect recurrent genomic changes that some 8, while the coding sequences of the second and third are relevant to pathogenesis of BL. We tested the tumorigeni- exon are translocated to, and rearranged with different regions city of these lines by injecting cells intraperitoneally in SCID of the IgH locus on chromosome.10 mice. In two separate experiments, CA46 cells produced Even though CA46 and ST486 lines have been used to tumors 2 weeks after cell inoculation while ST486 cells induced clone and sequence the translocated myc gene in BL, their only one tumor after a long latency period. Partial duplication 10 of the long arm of chromosome 1 involving variable bands but cytogenetic characterization was not reported. We analyzed always band 1q23 is the second most common alteration in BL these lines byseveral molecular cytogenetictechniques and and is known to be associated with aggressive tumors and found novel rearrangements involving c-myc gene and gen- poor prognosis. Duplication of the bands 1q23–24 commonly omic imbalances that maybe important to the pathogenesis observed in EBV-negative lines was identified only in highly of this malignancy. tumorigenic CA46 cells suggesting that this region harbor gene(s) associated with tumor cell invasiveness. Leukemia (2001) 15, 1582–1588. Materials and methods Keywords: Burkitt’s lymphoma; chromosome translocation; c-myc; comparative genomic hybridization; fluorescence in situ hybridiz- CA46 and ST486 cell lines derived from sporadic BL (ATCC, ation; spectral karyotyping Rockville, MD, USA) were cultivated in RPMI 1640 medium supplemented with 10% fetal bovine serum and antibiotics. Both lines are Epstein–Barr virus (EBV) nuclear antigen-nega- Introduction tive. Chromosomes were prepared using standard hypotonic KCl and methanol/acetic acid fixation procedures. A significant number of leukemias and lymphomas have spe- For CGH, DNA was isolated from cultured cells according cific reciprocal chromosomal translocations.1,2 Reciprocal to standard phenol-extraction protocols. Genomic DNA from translocations maylead to activation of proto-oncogenes or cell lines and from normal human cells, were labeled bynick- generate new oncogenic chimeric genes. As both oncogene translation with biotin (Bio-16-dUTP, Boehringer Mannheim, products and gene fusion proteins are often transcriptional Mannheim, Germany) and digoxigenin (Dig-11-dUTP, Boeh- factors, the disruption of transcription control might be a criti- ringer Mannheim), respectively, and hybridized to chromo- cal and etiologicallyrelevant alteration in the development of somes prepared from normal lymphocyte cultures. The orig- certain forms of neoplasia. In addition, fusion proteins are inal CGH protocol with minor modification as previously unique tumor antigens and are potential targets for therapy described in detail, was employed.6 design.2–5 SKY analysis was performed as previously described.11 Because recurrent chromosomal translocations provide Chromosome probe cocktail labeled bySpectrum Orange, cytogenetic and molecular markers for the diagnosis, prog- Texas Red, CY5, Spectrum Green, and Cy5.5, was denatured nosis and detection of minimal residual disease, theyhave and hybridized on denatured target slides. Visualization for been analyzed by a variety of molecular and conventional biotin- and digoxigenin-labeled DNAs of the probe-cocktail cytogenetic procedures. The advancements in molecular cyto- was carried out using avidin-Cy5 (Amersham, Piscataway, NJ, genetics through the development of FISH-based protocols for USA) and antidigoxigenin-Cy5.5 antibody (Sigma, St Louis, gene localization, global detection of genomic imbalances, MO, USA). An interferogram for each metaphase was gener- and multicolor visualization of structural chromosome ated using SD200 Spectracube (Applied Spectral Imaging, changes, have propelled the analysis of cancer cells to an Carlsbad, CA, USA) mounted on Zeiss Axioscope II fluor- unprecedented level of resolution.6,7 escent microscope equipped with custom-made optical filter Characteristic for Burkitt’s lymphoma (BL) are translocations (Chroma Technology, Brattleboro, VT, USA), and spectral information, upon recoverybyFourier transformation, was used to produce multicolor digital image with red, green and blue colors assigned to certain ranges of recorded spectrum. Correspondence: NC Popescu, National Cancer Institute, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255, USA; Fax: 301 496 Further analysis and classification were performed in SKY 0734 View 1. 5 karyotyping software (Applied Spectral Imaging) Received 7 March 2001; accepted 19 July2001 using a Windows NT Workstation. Genetic abnormalities in Burkitt’s lymphoma DB Zimonjic et al 1583 Biotin- and digoxigenin-labeled chromosomes 8 and 14 allowed an unequivocal identification of all structural painting and telomeric probes, chromosome-arm probes for rearrangements, including their precise derivation, as well as chromosome 1, a genomic myc probe (Oncor, Gaithersburg, the localization of breakpoints and genomic imbalances. MD, USA) as well as YAC probes for regions 1q21-q25 were SKY results are based on 20 complete multicolor karyotypes used for FISH. Detection of the hybridization signal, digital which include inverted DAPI banding for each of the meta- image acquisition, and analysis were carried out as pre- phases. G-banding analysis was based on 10 separate viouslydescribed. 12 trypsin/Giemsa-banded karyotypes in each line. Three clonal Cells derived from each line were tested for tumorigenicity subpopulations were observed in CA46 line. The largest sub- in SCID mice (NCI Breeding Facility, Bethesda, MD, USA). population of approximately50% of the cells, had reciprocal Each group of five animals, was injected intraperitoneallywith t(8;14)(q24;q32) translocation involving c-myc and IgH loci a 0.5 ml of suspension in complete medium containing 1 × (Figure 1a), an intrachromosomal rearrangement of chromo- 106 and 2 × 106 cells. Animals were examined weeklyfor some 1, and in the majorityof cells, trisomy16. A fraction of tumor growth. For histopathologic examination pieces of these cells had trisomy7 and most likelywere the progenitor tumor tissue were fixed in formalin buffer, embedded in paraf- of two other subpopulations carrying secondary translocations fin, cut, deparaffinized and stained with hematoxylin and t(7;8;14)(q11.2;q24;q32) and t(7;13)(q11;p11), both involving eosin. chromosome 7 (Figure 1b and c). These alterations resulted in loss of chromosome 7 material. In balanced t(8;14) translo- cation, the segment from chromosome 14 of approximately Results 150 Kb13 translocated on chromosome 8 was not visible by SKY or bypainting with chromosome 14 probe, but was The profile of cytogenetic alterations in CA46 and ST468 lines detected byFISH with chromosome 14 telomeric probe was determined bySKY, G-banding, CGH and FISH, shortly (Figure 2a). Cells with this karyotype, after hybridization with after the cells were received from ATCC, as well as after exten- myc genomic probe, had three signals on chromosome 8, sive subculturing. A combined molecular cytogenetic analysis der(8) and der(14) (Figure 2b). Secondaryt(7;814) translo- Figure 1 Spectral karyotyping (SKY) analysis of Burkitt’s lymphoma cell lines CA46 and ST486. (a) SKY karyotype of the predominant cell subpopulation from CA46 line. All of these cells have reciprocal t(8;14) translocation and alteration of chromosome 1. The segment from chromosome 14 translocated on chromosome 8 was not detected by SKY. (b) SKY karyotype of a second cell subpopulation from the CA46 line having a secondary t(7;8;14) translocation. (c) SKY karyotype of a third cell subpopulation from the CA46 line having a secondary t(7;13) translocation. (d) SKY karyoytpe of the ST486 cell line. As in CA46 cells the reciprocal t(8;14) translocations was not fully detected by SKY. Other abnormalities in these lines are two complex translocations: t(1;16) and t(8;14;18). Leukemia Genetic abnormalities in Burkitt’s lymphoma DB Zimonjic et al 1584 Figure 2 Fluorescence in situ hybridization (FISH) analysis of chromosomal translocations in CA46 and ST486 cell lines. (a) Metaphase from CA46 cell line carrying balanced t(8;14) translocation after FISH with 14-qter specific probe. Double fluorescent signals on the distal ends of one chromosome 14 and on der(8) are pointed byarrows. (b) Metaphase from CA46 cells exhibiting t(8;14) translocation, hybridizedwith c- myc probe. Signals for myc gene are on chromosome 8, der(8), and der(14) (arrows). (c) Metaphase from CA46 cells exhibiting a secondary t(7;8;14) translocation, hybridized with c-myc probe.
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