Dysregulation of c-maf is associated with t(14,-16)(q32;q23) breakpoints that flank the FRA 16D fragile site within the WWOX gene, and can be greater than 1 MB from c-MAF

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Abstract

Most multiple myeloma (MM) tumors have IgH (14q32) translocations, with breakpoints typically dispersed over regions up to 350 kb centromeric to the dysregulated oncogene that is located on the partner chromosome. The t(14;16)(q32;q23) occurs in about 10% of MM tumors, and is unusual because breakpoints appear to be located as far as 1 Mb from the c-maf oncogene, which is over-expressed only when there is an Ig translocation involving this locus. The 16q23 region that contains these 5 breakpoints is notable in that it includes the approximately 1 Mb WWOX/FOR oxidoreductase gene and the Fral6D fragile site. Four breakpoints (MM.l, OC1-MY5, JJN3, and ANBL6) are dispersed over a 300 kb region telomeric to FraloD, within the 800 kb intron 8 of WWOX. In germline DNA, the location of these sites is at > 350-650 kb from c-maf. The other breakpoint (KMS11 ) is located in intron 5 of WWOX, at a site that is at least 1 Mb from c-maf in germline DNA. Given the frequent occurrence of 16q23 deletions seen in many kinds of tumors, it is possible that the t( 14; 16) in MM is associated with deletions, so that c-maf is closer to the breakpoints than in germline DNA. Using a contig of BAC clones that encompass the region between c-maf and the most centromeric breakpoint, we did metaphase FISH mapping to show that all of the 16q23 sequences in this region are present on one of the two translocation derivatives, with no detectable internal deletions. However, in 2 of 5 MM cell lines, we did find internal deletions involving this I6q23 region on copies of chromosome 16 not involved in the translocation. The pattern of expression of WWOX mRNA was similar in these 5 lines and in 10 MM cell lines not having a t(14;16), with two exceptions: KMSl 1 (which has a translocation or internal deletion affecting all WWOX alleles), and also one of the MM lines lacking a t(14;16). It has been suggested that WWOX might be a tumor suppressor gene, with one allele lost as a result of a deletion or translocation, and the other allele inactivated by a missense mutation. We analyzed 3 lines (MM.l, OCI-MY5, and ANBL6) that have one allele disrupted by a t(14;16), but found no missense mutations in WWOX mRNA.

Original languageEnglish (US)
JournalBlood
Volume96
Issue number11 PART II
StatePublished - 2000

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Proto-Oncogene Proteins c-fos
Multiple Myeloma
Tumors
Genes
Chromosomes
Introns
DNA
Alleles
Cells
Messenger RNA
Missense Mutation
Oncogenes
Oxidoreductases
Derivatives
Chromosomes, Human, Pair 16
Cell Line
Neoplasms
Metaphase
Tumor Suppressor Genes
Clone Cells

ASJC Scopus subject areas

  • Hematology

Cite this

@article{51ca953a64184bd3a5737a85219c8f47,
title = "Dysregulation of c-maf is associated with t(14,-16)(q32;q23) breakpoints that flank the FRA 16D fragile site within the WWOX gene, and can be greater than 1 MB from c-MAF",
abstract = "Most multiple myeloma (MM) tumors have IgH (14q32) translocations, with breakpoints typically dispersed over regions up to 350 kb centromeric to the dysregulated oncogene that is located on the partner chromosome. The t(14;16)(q32;q23) occurs in about 10{\%} of MM tumors, and is unusual because breakpoints appear to be located as far as 1 Mb from the c-maf oncogene, which is over-expressed only when there is an Ig translocation involving this locus. The 16q23 region that contains these 5 breakpoints is notable in that it includes the approximately 1 Mb WWOX/FOR oxidoreductase gene and the Fral6D fragile site. Four breakpoints (MM.l, OC1-MY5, JJN3, and ANBL6) are dispersed over a 300 kb region telomeric to FraloD, within the 800 kb intron 8 of WWOX. In germline DNA, the location of these sites is at > 350-650 kb from c-maf. The other breakpoint (KMS11 ) is located in intron 5 of WWOX, at a site that is at least 1 Mb from c-maf in germline DNA. Given the frequent occurrence of 16q23 deletions seen in many kinds of tumors, it is possible that the t( 14; 16) in MM is associated with deletions, so that c-maf is closer to the breakpoints than in germline DNA. Using a contig of BAC clones that encompass the region between c-maf and the most centromeric breakpoint, we did metaphase FISH mapping to show that all of the 16q23 sequences in this region are present on one of the two translocation derivatives, with no detectable internal deletions. However, in 2 of 5 MM cell lines, we did find internal deletions involving this I6q23 region on copies of chromosome 16 not involved in the translocation. The pattern of expression of WWOX mRNA was similar in these 5 lines and in 10 MM cell lines not having a t(14;16), with two exceptions: KMSl 1 (which has a translocation or internal deletion affecting all WWOX alleles), and also one of the MM lines lacking a t(14;16). It has been suggested that WWOX might be a tumor suppressor gene, with one allele lost as a result of a deletion or translocation, and the other allele inactivated by a missense mutation. We analyzed 3 lines (MM.l, OCI-MY5, and ANBL6) that have one allele disrupted by a t(14;16), but found no missense mutations in WWOX mRNA.",
author = "Rafael Fonseca",
year = "2000",
language = "English (US)",
volume = "96",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "11 PART II",

}

TY - JOUR

T1 - Dysregulation of c-maf is associated with t(14,-16)(q32;q23) breakpoints that flank the FRA 16D fragile site within the WWOX gene, and can be greater than 1 MB from c-MAF

AU - Fonseca, Rafael

PY - 2000

Y1 - 2000

N2 - Most multiple myeloma (MM) tumors have IgH (14q32) translocations, with breakpoints typically dispersed over regions up to 350 kb centromeric to the dysregulated oncogene that is located on the partner chromosome. The t(14;16)(q32;q23) occurs in about 10% of MM tumors, and is unusual because breakpoints appear to be located as far as 1 Mb from the c-maf oncogene, which is over-expressed only when there is an Ig translocation involving this locus. The 16q23 region that contains these 5 breakpoints is notable in that it includes the approximately 1 Mb WWOX/FOR oxidoreductase gene and the Fral6D fragile site. Four breakpoints (MM.l, OC1-MY5, JJN3, and ANBL6) are dispersed over a 300 kb region telomeric to FraloD, within the 800 kb intron 8 of WWOX. In germline DNA, the location of these sites is at > 350-650 kb from c-maf. The other breakpoint (KMS11 ) is located in intron 5 of WWOX, at a site that is at least 1 Mb from c-maf in germline DNA. Given the frequent occurrence of 16q23 deletions seen in many kinds of tumors, it is possible that the t( 14; 16) in MM is associated with deletions, so that c-maf is closer to the breakpoints than in germline DNA. Using a contig of BAC clones that encompass the region between c-maf and the most centromeric breakpoint, we did metaphase FISH mapping to show that all of the 16q23 sequences in this region are present on one of the two translocation derivatives, with no detectable internal deletions. However, in 2 of 5 MM cell lines, we did find internal deletions involving this I6q23 region on copies of chromosome 16 not involved in the translocation. The pattern of expression of WWOX mRNA was similar in these 5 lines and in 10 MM cell lines not having a t(14;16), with two exceptions: KMSl 1 (which has a translocation or internal deletion affecting all WWOX alleles), and also one of the MM lines lacking a t(14;16). It has been suggested that WWOX might be a tumor suppressor gene, with one allele lost as a result of a deletion or translocation, and the other allele inactivated by a missense mutation. We analyzed 3 lines (MM.l, OCI-MY5, and ANBL6) that have one allele disrupted by a t(14;16), but found no missense mutations in WWOX mRNA.

AB - Most multiple myeloma (MM) tumors have IgH (14q32) translocations, with breakpoints typically dispersed over regions up to 350 kb centromeric to the dysregulated oncogene that is located on the partner chromosome. The t(14;16)(q32;q23) occurs in about 10% of MM tumors, and is unusual because breakpoints appear to be located as far as 1 Mb from the c-maf oncogene, which is over-expressed only when there is an Ig translocation involving this locus. The 16q23 region that contains these 5 breakpoints is notable in that it includes the approximately 1 Mb WWOX/FOR oxidoreductase gene and the Fral6D fragile site. Four breakpoints (MM.l, OC1-MY5, JJN3, and ANBL6) are dispersed over a 300 kb region telomeric to FraloD, within the 800 kb intron 8 of WWOX. In germline DNA, the location of these sites is at > 350-650 kb from c-maf. The other breakpoint (KMS11 ) is located in intron 5 of WWOX, at a site that is at least 1 Mb from c-maf in germline DNA. Given the frequent occurrence of 16q23 deletions seen in many kinds of tumors, it is possible that the t( 14; 16) in MM is associated with deletions, so that c-maf is closer to the breakpoints than in germline DNA. Using a contig of BAC clones that encompass the region between c-maf and the most centromeric breakpoint, we did metaphase FISH mapping to show that all of the 16q23 sequences in this region are present on one of the two translocation derivatives, with no detectable internal deletions. However, in 2 of 5 MM cell lines, we did find internal deletions involving this I6q23 region on copies of chromosome 16 not involved in the translocation. The pattern of expression of WWOX mRNA was similar in these 5 lines and in 10 MM cell lines not having a t(14;16), with two exceptions: KMSl 1 (which has a translocation or internal deletion affecting all WWOX alleles), and also one of the MM lines lacking a t(14;16). It has been suggested that WWOX might be a tumor suppressor gene, with one allele lost as a result of a deletion or translocation, and the other allele inactivated by a missense mutation. We analyzed 3 lines (MM.l, OCI-MY5, and ANBL6) that have one allele disrupted by a t(14;16), but found no missense mutations in WWOX mRNA.

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