Three breakpoints of variant t(2;8) translocations in Burkitt''s lymphoma cells fall within a region 140 kilobases distal from c-myc.

The variant translocations t(2;8) in Burkitt's lymphoma cells join band q24 of chromosome 8, distal from c-myc, to the Igkappa locus, with considerable variation in the location of the breakpoints on chromosome 8. We report the cloning and molecular characterization of a chromosome 8 region, distal from the c-myc locus, which encompasses the breakpoints of the Burkitt's lymphoma cell lines BL64, BL21, and LY91 within 11 kilobase pairs, termed provisionally bvr-1 (Burkitt's variants' rearranging region 1). Using probes from the c-myc, the bvr-1, and the human pvt-1 loci obtained by chromosome walking coupled with pulsed-field gel electrophoresis, we have constructed a physical map of the region 3' of c-myc. We map bvr-1 and pvt-1 about 140 and 260 kilobase pairs, respectively, distal from c-myc.     

The t(8;14) breakpoint of the EW 36 undifferentiated lymphoma cell line lies 5' of MYC in a region prone to involvement in endemic Burkitt's lymphomas

One of the best analyzed tumor-specific cytogenetic abnormalities is the t(8;14) chromosomal translocation observed in cases of Burkitt's and undifferentiated lymphomas (ULs), and acute lymphoblastic leukemias (ALLs). Here we analyze the cloned (8;14) chromosomal breakpoint of the UL cell line EW 36. We show that the region of chromosome 8 involved in the translocation is situated near a site previously demonstrated to harbor a cluster of endemic Burkitt's lymphoma breakpoints, approximately 50 kb 5' of MYC. In those cases, we demonstrated that malfunction of the V-D-J recombinase generated the translocations. However, in this case the isotype switch mechanism of translocation is implicated: at the breakpoint, S mu/S gamma and C gamma sequences are found on chromosome 14. Thus, the features of the EW 36 t(8;14) breakpoint are consonant with our model for B-cell lymphomagenesis which relates the precursor cell that gives rise to malignancy, the mechanism of translocation, and the phenotype of the tumor.     

The PVT gene frequently amplifies with MYC in tumor cells.

The line of human colon carcinoma cells known as COLO320-DM contains an amplified and abnormal allele of the proto-oncogene MYC (DMMYC). Exon 1 and most of intron 1 of MYC have been displaced from DMMYC by a rearrangement of DNA. The RNA transcribed from DMMYC is a chimera that begins with an ectopic sequence of 176 nucleotides and then continues with exons 2 and 3 of MYC. The template for the ectopic sequence represents exon 1 of a gene known as PVT, which lies 50 kilobase pairs downstream of MYC. We encountered three abnormal configurations of MYC and PVT in the cell lines analyzed here: (i) amplification of the genes, accompanied by insertion of exon 1 and an undetermined additional portion of PVT within intron 1 of MYC to create DMMYC; (ii) selective deletion of exon 1 of PVT from amplified DNA that contains downstream portions of PVT and an intact allele of MYC; and (iii) coamplification of MYC and exon 1 of PVT, but not of downstream portions of PVT. We conclude that part or all of PVT is frequently amplified with MYC and that intron 1 of PVT represents a preferred boundary for amplification affecting MYC.     

The novel ETS factor TEL2 cooperates with Myc in B lymphomagenesis

The human ETS family gene TEL2/ETV7 is highly homologous to TEL1/ETV6, a frequent target of chromosome translocations in human leukemia and specific solid tumors. Here we report that TEL2 augments the proliferation and survival of normal mouse B cells and dramatically accelerates lymphoma development in Emu-Myc transgenic mice. Nonetheless, inactivation of the p53 pathway was a hallmark of all TEL2/Emu-Myc lymphomas, indicating that TEL2 expression alone is insufficient to bypass this apoptotic checkpoint. Although TEL2 is infrequently up-regulated in human sporadic Burkitt's lymphoma, analysis of pediatric B-cell acute lymphocytic leukemia (B-ALL) samples showed increased coexpression of TEL2 and MYC and/or MYCN in over one-third of B-ALL patients. Therefore, TEL2 and MYC also appear to cooperate in provoking a cadre of human B-cell malignancies.     

Cytogenetic studies in 30 patients with Burkitt's lymphoma or L3 acute lymphoblastic leukemia with special reference to additional chromosome abnormalities

We performed cytogenetic analysis in 23 consecutive patients with Burkitt's ALL and 7 patients with Burkitt's lymphoma. Only one patient had a normal karyotype. Twenty-seven patients had a (8;14) translocation and 2 a (2;8) translocation. No (8;22) translocation was seen. In 12 patients (41%), the t(8;14) was the only chromosome rearrangement whereas in the 18 remaining cases (59%), the t(8;14) or t(2;8) was associated with other numerical or structural abnormalities. Chromosomes 1, 7 and 6 were rearranged in 10, 8, and 5 patients, respectively, usually in translocations, duplications, deletions (chromosome 6), or isochromosome of the long arm (chromosomes 1 or 7). The incidence of these additional rearrangements is discussed with regard to previously published reports and the chromosome localization of oncogenes.     

Lambda Ig constant region genes are translocated to chromosome 8 in Burkitt''s lymphoma with t(8;22)

By in situ hybridization of normal human chromosomes with a cloned genomic probe specific for the constant region of the lambda immunoglobulin genes, band 22q11 was preferentially labelled. In two cell lines with t(8;22) derived from Burkitt's lymphoma a strong signal was noted on the 8q+ chromosome derivative, indicating that the constant region of the lambda Ig gene cluster was translocated from chromosome 22 to chromosome 8. In addition, the signal observed on the 22q- derivative chromosome was stronger than the background in one of the two cell lines tested, but not in the other. The implications are that the break point in chromosome 22 in some cases lies within the Ig gene itself or between clusters of such genes, and that different cases have different break points.     

Is there a functional equivalence between abnormalities of the long arm of chromosome 1 and the presence of Epstein-Barr virus in continuous lines of Burkitt's lymphoma?

Chromosome 1 long arm abnormalities (translocations, partial of complete trisomies) are non-randomly but inconstantly associated with specific translocations involving chromosomes 8, and 2, 14 or 22 in Burkitt's lymphomas and leukemias. All nine Burkitt's lymphoma cell lines not associated with Epstein-Barr virus (EBV) were shown to exhibit a chromosome 1 long arm abnormality and were present in only 3 out of 18 EBV positive cell lines. Bands 1q23 - 1q24 were involved in EBV-negative cell lines. It was thus hypothesised that genetic information resembling that included in viral genome exists on chromosome 1 long arm. This hypothesis implies new possible aspects of relationship between Burkitt's cell line proliferation and EBV.     

Aberrant c-myc RNAs of Burkitt's lymphoma cells have longer half-lives.

BL67 and BL18 are Burkitt's lymphoma cell lines with t(8;14) translocations (the breakpoint is in the first exon and first intron, respectively) in which the mu-heavy chain switch region is fused to the c-myc gene in head to head orientation. In both cell lines only aberrant c-myc RNAs are found. BL67 cells contain two c-myc RNA species of 2.4 and 3.5 kb. The 2.4-kb RNA is initiated at several cryptic promoters in the first intron. The 3.5-kb RNA is transcribed from the immunoglobulin heavy chain anti-sense strand across the breakpoint of the translocation into the first exon of the c-myc gene and is then normally spliced using the physiological splice donor and acceptor sites of the c-myc gene. BL18 contains c-myc RNA of 2.4 kb initiated at cryptic promoters in the first intron and additional RNAs of 0.90 kb and 0.74 kb transcribed from the dual c-myc promoters on the reciprocal fragment of the translocation. The cytoplasmic turnover of these RNAs differs significantly from that of the normal c-myc message. The 3.5-kb RNA of BL67 cells and the 0.90-kb and 0.74-kb RNAs of BL18 cells, which are both hybrid molecules consisting of c-myc and immunoglobulin sequences, have a half-life of several hours in contrast to the normal c-myc message with a half-life of 15 min. The aberrant 2.4-kb c-myc RNAs of BL67 and BL18 cells are also more stable than the normal c-myc message and disappear with a half-life of 50 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

c-myc and immunoglobulin kappa light chain constant genes are on the 8q+ chromosome of three Burkitt lymphoma lines with t(2;8) translocations.

We have determined the localization of c-myc and the immunoglobulin kappa light chain genes on the 8q+/2p- chromosomes of the three Burkitt lymphoma lines BL21, LY66 and LY91 with t(2;8) translocation by in situ hybridization. BL21 is characterized by a complex translocation in which a piece of chromosome 9 appears to be located between the fragments of chromosome 8 and 2 on the 8q+ chromosome. Our data indicate that in all three cell lines the c-myc gene is located on the 8q+ chromosome proximal to the breakpoint in band 8q24. In all cell lines examined the cluster of kappa variable genes has remained on the 2p- chromosome. In LY91 cells the major part of the joining region remained on 2p-, while the joining region has moved to 8q+ in the cell lines BL21 and LY66. In all three cell lines the constant kappa light chain gene was found on the 8q+ chromosome. The fact that an essentially identical pattern was found in the cell line BL21, with the complex translocation, suggests that the insertion of the piece of chromosome 9 into the 8q+ chromosome might be a secondary event. Our present data fit into the concept that in all Burkitt lymphoma lines investigated so far, including cases with t(8;14) and the variant translocations t(2;8) and t(8;22), the c-myc gene becomes situated at the 5' side of an immunoglobulin constant gene. This may have implications for the generation of somatic mutations in the coding and non-coding part of the c-myc gene.     

A 1.5-megabase restriction map surrounding MYC does not include the translocation breakpoint in familial renal cell carcinoma

A constitutional translocation t(3;8)(p14.2;q24.1) segregates concordantly with a familial form of renal cell carcinoma (RCC). This translocation moves the MYC oncogene, located at 8q24.1, onto the short arm of chromosome 3. Chromosome rearrangements that break in or near MYC can result in altered expression of this gene and are thought to be a primary change leading to the transformed phenotype in certain neoplastic diseases, particularly Burkitt lymphoma. Possible rearrangements of this gene in familial RCC have so far not been detected using standard Southern blot analysis. We used pulsed field gel (PFG) analysis to construct a restriction map that covers a 1500-kb region surrounding MYC, including over 1000 kb to the 5' and 550 kb to the 3' side of this gene. The 5' end of MYC contains a cluster of cleavage sites for rare-cutting restriction endonucleases, indicating the presence of an HTF island. PFG analysis of DNA containing the t(3;8) rearrangement shows that the breakpoint is not located in the mapped region, making it unlikely that MYC is involved in this form of renal cell carcinoma. The map should facilitate study of other chromosome 8 rearrangements thought to break near MYC.     

AID is required for c-myc/IgH chromosome translocations in vivo

Chromosome translocations between c-myc and immunoglobulin (Ig) are associated with Burkitt's lymphoma in humans and with pristane- and IL6-induced plasmacytomas in mice. These translocations frequently involve Ig switch regions, suggesting that they might be the result of aberrant Ig class switch recombination (CSR). However, a direct link between CSR and chromosome translocations has not been established. We have examined c-myc/IgH translocations in IL6 transgenic mice that are mutant for activation induced cytidine deaminase (AID), the enzyme that initiates CSR. Here we report that AID is essential for the c-myc/IgH chromosome translocations induced by IL6.     

Cytological and cytogenetical studies on brain tumors. VI. No evidence for a translocation in 22-monosomic meningiomas.

The recently detected reciprocal translocations in chronic myeloic leucemia (CML) and Burkitt's lymphoma (BL) made it necessary to clarify if meningiomas really show the described monosomy 22 or also a translocation. In 10 out of 12 meningiomas a total or partial translocation of the missing chromosome 22 to another chromosome could be ruled out by fluorescence banding analysis. Two meningiomas showed marker chromosomes of such a complex composition that it was impossible to decide if a 22 translocation was present or not. From these results it was concluded that meningioma cells, in contrast to CML and BL, show almost regularly a loss of a definitive part of their genome.     

The rat MIS1/Pvt-1 locus is syntenic with MYC on chromosome 7

Mouse Pvt-1 and rat MIS1 are frequent proviral integration sites in retrovirally induced lymphomas. The Pvt-1 locus is also involved in mouse plasmacytoma (6;15) and in the variant Burkitt lymphoma (2;8) translocations. We show that the Pvt-1/MIS1 locus is syntenic with MYC on rat chromosome 7. This is consistent with a postulate of close linkage and, possibly, a functional relationship between the MYC protooncogene and the MIS1/Pvt-1 locus.