6;7 chromosomal translocation in spontaneously arising rat immunocytomas: evidence for c-myc breakpoint clustering and correlation between isotypic expression and the c-myc target.

Our previous studies have shown that spontaneously arising immunocytomas in the LOU/Ws1 strain of rats contain a t(6;7) chromosomal translocation in all seven tumors studied (F. M. Babonits, J. Spira, G. Klein, and H. Bazin, Int. J. Cancer 29:431-437, 1982). We have also shown that the c-myc is located on chromosome 7 (J. Sümegi, J. Spira, H. Bazin, J. Szpirer, G. Levan, and G. Klein, Nature (London) 306:497-499, 1983) and the immunoglobulin H cluster on chromosome 6 (W.S. Pear, G. Wahlström, J. Szpirer, G. Levan, G. Klein, and J. Sümegi, Immunogenetics 23:393-395, 1986). We now report a detailed cytogenetic and molecular analysis of nine additional rat immunocytomas. The t(6;7) chromosomal translocation is found in all tumors. Mapping of the c-myc breakpoints showed that in 10 of 14 tumors, the c-myc breakpoints are clustered in a 1.5-kilobase region upstream of exon 1. In contrast with sporadic Burkitt's lymphoma and mouse plasmacytoma, only 1 of 14 tumors contains the c-myc breakpoints in either exon 1 or intron 1. Analysis of the sequences juxtaposed to the c-myc show that immunoglobulin H switch regions are the targets in at least five tumors and that there is a strong correlation between the secreted immunoglobulin and the c-myc target. Unlike sporadic Burkitt's lymphoma and mouse plasmacytoma, at least two rat immunocytomas show recombination of the c-myc with sequences distinct from immunoglobulin switch regions.

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c-myc hypermutation is ongoing in endemic, but not all Burkitt's lymphoma

Blood ◽

10.1182/blood.v78.9.2419.2419 ◽

1991 ◽

Vol 78 (9) ◽

pp. 2419-2425 ◽

Cited By ~ 15

Author(s):

JM Johnston ◽

MT Yu ◽

WL Carroll

Keyword(s):

Chromosomal Translocation ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Random Pattern ◽

Immunoglobulin Gene ◽

Protein Coding ◽

Myc Oncogene ◽

Eukaryotic Gene ◽

Exon 1 ◽

Tumor Clone

Abstract Deregulation of c-myc oncogene secondary to chromosomal translocation appears to play an essential role in the genesis of both endemic (African) Burkitt's lymphoma (eBL) and sporadic Burkitt's lymphoma (sBL). In most eBL, mutations in or near exon 1 disrupt normal c-myc regulatory sites. We examined c-myc sequences from a patient with sBL and two patients with eBL to determine (1) whether mutation is ongoing as the tumor clone expands, (2) the nature of mutations in the protein- coding exons 2 and 3, and (3) the extent of c-myc hypermutation in the two clinical forms of BL. Using the polymerase chain reaction (PCR), we amplified segments of c-myc from bulk tumor samples, cloned the products into plasmid vectors, and sequenced multiple subclones of each segment. The mutation frequencies in the control (remission bone marrow) and sBL tumor subclones were 0.65 x 10(-4) and 3.0 x 10(-4) (mutations/base), respectively (P greater than .25). Subclones from the two eBLs exhibited mutation frequencies of 20 x 10(-4) and 16 x 10(-4), respectively (P less than .001 v control). In addition to the consensus mutations seen in one eBL, a random pattern of unshared mutations was observed throughout c-myc in both samples, demonstrating that mutations may be introduced in a stepwise fashion. We noted a clear excess of transitions over transversions (30:9), which is qualitatively similar to the pattern observed in diverse examples of eukaryotic gene mutation. These data demonstrate that c-myc hypermutation is an ongoing process as the eBL tumor clone expands, is qualitatively different from immunoglobulin gene hypermutation, and is not a universal feature of BL, perhaps reflecting the nature of the translocation or the stage of tumor cell maturation.

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c-myc hypermutation is ongoing in endemic, but not all Burkitt's lymphoma

Blood ◽

10.1182/blood.v78.9.2419.bloodjournal7892419 ◽

1991 ◽

Vol 78 (9) ◽

pp. 2419-2425 ◽

Cited By ~ 1

Author(s):

JM Johnston ◽

MT Yu ◽

WL Carroll

Keyword(s):

Chromosomal Translocation ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Random Pattern ◽

Immunoglobulin Gene ◽

Protein Coding ◽

Myc Oncogene ◽

Eukaryotic Gene ◽

Exon 1 ◽

Tumor Clone

Deregulation of c-myc oncogene secondary to chromosomal translocation appears to play an essential role in the genesis of both endemic (African) Burkitt's lymphoma (eBL) and sporadic Burkitt's lymphoma (sBL). In most eBL, mutations in or near exon 1 disrupt normal c-myc regulatory sites. We examined c-myc sequences from a patient with sBL and two patients with eBL to determine (1) whether mutation is ongoing as the tumor clone expands, (2) the nature of mutations in the protein- coding exons 2 and 3, and (3) the extent of c-myc hypermutation in the two clinical forms of BL. Using the polymerase chain reaction (PCR), we amplified segments of c-myc from bulk tumor samples, cloned the products into plasmid vectors, and sequenced multiple subclones of each segment. The mutation frequencies in the control (remission bone marrow) and sBL tumor subclones were 0.65 x 10(-4) and 3.0 x 10(-4) (mutations/base), respectively (P greater than .25). Subclones from the two eBLs exhibited mutation frequencies of 20 x 10(-4) and 16 x 10(-4), respectively (P less than .001 v control). In addition to the consensus mutations seen in one eBL, a random pattern of unshared mutations was observed throughout c-myc in both samples, demonstrating that mutations may be introduced in a stepwise fashion. We noted a clear excess of transitions over transversions (30:9), which is qualitatively similar to the pattern observed in diverse examples of eukaryotic gene mutation. These data demonstrate that c-myc hypermutation is an ongoing process as the eBL tumor clone expands, is qualitatively different from immunoglobulin gene hypermutation, and is not a universal feature of BL, perhaps reflecting the nature of the translocation or the stage of tumor cell maturation.

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Somatic mutation and transcriptional deregulation of myc in endemic Burkitt's lymphoma disease: heptamer-nonamer recognition mistakes?

Molecular and Cellular Biology ◽

10.1128/mcb.9.1.74-82.1989 ◽

1989 ◽

Vol 9 (1) ◽

pp. 74-82

Author(s):

B Morse ◽

V J South ◽

P G Rothberg ◽

S M Astrin

Keyword(s):

Somatic Mutation ◽

Sequence Data ◽

Burkitt’S Lymphoma ◽

Complete Sequence ◽

Burkitt's Lymphoma ◽

Recognition Sequence ◽

Intron 1 ◽

Exon 1 ◽

Transcriptional Deregulation ◽

Lymphoma Sample

We examined the structure and expression of the myc protooncogene in DNA extracted from a primary (uncultured) endemic Burkitt's lymphoma sample designated eBL3. Dot and Northern (RNA) blot analyses demonstrated extreme levels of myc RNA in the eBL3 sample. Nearly complete sequence data of the altered myc locus isolated from eBL3 DNA demonstrated extensive mutations (duplications, insertions, and deletions) in critical myc regulatory regions. Taken together, the data support the idea that myc transcriptional deregulation in Burkitt's lymphoma disease may be a consequence of the position and number of mutations produced within and around the myc locus. Furthermore, the myc exon-1-intron-1 hypermutable PvuII site is part of a potential heptamer-nonamer recognition sequence, suggesting a mechanism for mutation in endemic Burkitt's lymphoma disease.

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Somatic mutation and transcriptional deregulation of myc in endemic Burkitt's lymphoma disease: heptamer-nonamer recognition mistakes?

Molecular and Cellular Biology ◽

10.1128/mcb.9.1.74 ◽

1989 ◽

Vol 9 (1) ◽

pp. 74-82 ◽

Cited By ~ 16

Author(s):

B Morse ◽

V J South ◽

P G Rothberg ◽

S M Astrin

Keyword(s):

Somatic Mutation ◽

Sequence Data ◽

Burkitt’S Lymphoma ◽

Complete Sequence ◽

Burkitt's Lymphoma ◽

Recognition Sequence ◽

Intron 1 ◽

Exon 1 ◽

Transcriptional Deregulation ◽

Lymphoma Sample

We examined the structure and expression of the myc protooncogene in DNA extracted from a primary (uncultured) endemic Burkitt's lymphoma sample designated eBL3. Dot and Northern (RNA) blot analyses demonstrated extreme levels of myc RNA in the eBL3 sample. Nearly complete sequence data of the altered myc locus isolated from eBL3 DNA demonstrated extensive mutations (duplications, insertions, and deletions) in critical myc regulatory regions. Taken together, the data support the idea that myc transcriptional deregulation in Burkitt's lymphoma disease may be a consequence of the position and number of mutations produced within and around the myc locus. Furthermore, the myc exon-1-intron-1 hypermutable PvuII site is part of a potential heptamer-nonamer recognition sequence, suggesting a mechanism for mutation in endemic Burkitt's lymphoma disease.

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The c-myc Gene Paradox in Burkitt’s Lymphoma Chromosomal Translocation

Oncogenes in B-Cell Neoplasia - Current Topics in Microbiology and Immunology ◽

10.1007/978-3-642-69860-6_28 ◽

1984 ◽

pp. 166-171 ◽

Cited By ~ 7

Author(s):

T. H. Rabbitts ◽

R. Baer ◽

M. Davis ◽

A. Forster ◽

P. H. Hamlyn ◽

...

Keyword(s):

Chromosomal Translocation ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Myc Gene

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Molecular Analysis of an AIDS-Associated Burkitt’s Lymphoma: Near-Identity with Endemic Cases

Current Topics in Microbiology and Immunology - Mechanisms in B-Cell Neoplasia 1988 ◽

10.1007/978-3-642-74006-0_11 ◽

1988 ◽

pp. 75-79 ◽

Cited By ~ 2

Author(s):

F. G. Haluska ◽

G. Russo ◽

M. Andreeff ◽

C. M. Croce

Keyword(s):

Molecular Analysis ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma

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Allele-specific activation of the c-myc gene in an atypical Burkitt's lymphoma carrying the t(2;8) chromosomal translocation 250 kb downstream from c-myc

Gene ◽

10.1016/0378-1119(93)90398-m ◽

1993 ◽

Vol 124 (2) ◽

pp. 231-237 ◽

Cited By ~ 7

Author(s):

Kouichi Tachibana ◽

Nobuyuki Takayama ◽

Koichi Matsuo ◽

Shingo Kato ◽

Kotaro Yamamoto ◽

...

Keyword(s):

Chromosomal Translocation ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Myc Gene ◽

Allele Specific

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p16/INK4a and p15/INK4b Gene Methylation and Absence of p16/INK4a mRNA and Protein Expression in Burkitt's Lymphoma

Blood ◽

10.1182/blood.v91.5.1680.1680_1680_1687 ◽

1998 ◽

Vol 91 (5) ◽

pp. 1680-1687 ◽

Cited By ~ 5

Author(s):

Ulf Klangby ◽

Ismail Okan ◽

Kristinn P. Magnusson ◽

Martin Wendland ◽

Peter Lind ◽

...

Keyword(s):

Cell Lines ◽

Low Frequency ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Lymphoblastoid Cell Lines ◽

Gene Methylation ◽

The Status ◽

Exon 1 ◽

Mrna And Protein Expression ◽

P16 Ink4a

The fact that the p16/INK4a and p15/INK4b genes are frequently inactivated in human malignancies and that p16/INK4a null mice spontaneously develop B-cell lymphomas prompted us to examine the status of both genes in Burkitt's Lymphoma (BL). We found a low frequency of p16/INK4a and p15/INK4b deletions and mutations in BL cell lines and biopsies. However, p16/INK4a exon 1 was methylated in 17 out of 19 BL lines (89.5%) and in 8 out of 19 BL biopsies (42%) analyzed. p15/INK4b Exon 1 was also methylated, although at a lower frequency. p16/INK4a mRNA was readily detected in BL lines carrying unmethylated p16/INK4a, but not in those carrying methylated p16/INK4a. No p16/INK4a protein was detected in any of the BL lines and biopsies examined. In contrast, only one out of seven lymphoblastoid cell lines (LCLs) examined was methylated in p16/INK4a exon 1, and three out of the six LCLs with unmethylated p16/INK4a expressed detectable levels of p16/INK4a protein. Thus, the frequent p16/INK4a methylation in BL lines correlates with downregulation of p16/INK4a expression, suggesting that exon 1 methylation is responsible for silencing the p16/INK4a gene in BL.

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