Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma

John Shaughnessy, Ana Gabrea, Ying Qi, Leslie Brents, Fenghaung Zhan, Erming Tian, Jeffrey Sawyer, Bart Barlogie, Peter Leif Bergsagel, Michael Kuehl

Research output: Contribution to journalArticle

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Abstract

Reciprocal chromosomal translocations, which are mediated by errors in immunoglobulin heavy chain (IgH) switch recombination or somatic hypermutation as plasma cells are generated in germinal centers, are present in most multiple myeloma (MM) tumors. These translocations dysregulate an oncogene that is repositioned in proximity to a strong IgH enhancer. There is a promiscuous array of nonrandom chromosomal partners (and oncogenes), with the 3 most frequent partners (11q13 [cyclin D1]; 4p16 [FGFR3 and MMSET]; 16q23 [c-maf]) involved in nearly half of MM tumors. It is now shown that a novel t(6;14)(p21;q32) translocation is present in 1 of 30 MM cell lines and that this cell line uniquely overexpresses cyclin D3. The cloned breakpoint juxta-poses gamma 4 switch sequences with 6p21 sequences that are located about 65 kb centromeric to the cyclin D3 gene. By metaphase chromosome analysis, the t(6;14) (p21;q32) translocation was identified in 6 of 150 (4%) primary MM tumors. Overexpression of cyclin D3 messenger RNA (mRNA) was identified by microarray RNA expression analysis in 3 of 53 additional primary MM tumors, each of which was found to have a t(6;14) translocation breakpoint by interphase fluorescence in situ hybridization analysis. One tumor has a t(6;22)(p21;q11) translocation, so that cyclin D3 is bracketed by the IgL and IgH breakpoints. These results provide the first clear evidence for primary dysregulation of cyclin D3 during tumorigenesis. It is suggested that the initial oncogenic event for most MM tumors is a primary immunoglobulin translocation that dysregulates cyclin D1, cyclin D3, and other oncogenes to provide a proliferative stimulus to postgerminal center plasma cells.

Original languageEnglish (US)
Pages (from-to)217-223
Number of pages7
JournalBlood
Volume98
Issue number1
DOIs
StatePublished - Jul 1 2001
Externally publishedYes

Fingerprint

Cyclin D3
Genetic Translocation
Multiple Myeloma
Immunoglobulins
Tumors
Immunoglobulin Heavy Chains
Oncogenes
Neoplasms
Cyclin D1
Plasma Cells
Cells
Switches
Plasmas
Cell Line
Germinal Center
Interphase
Metaphase
Microarrays
Chromosomes
Fluorescence In Situ Hybridization

ASJC Scopus subject areas

  • Hematology

Cite this

Shaughnessy, J., Gabrea, A., Qi, Y., Brents, L., Zhan, F., Tian, E., ... Kuehl, M. (2001). Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood, 98(1), 217-223. https://doi.org/10.1182/blood.V98.1.217

Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. / Shaughnessy, John; Gabrea, Ana; Qi, Ying; Brents, Leslie; Zhan, Fenghaung; Tian, Erming; Sawyer, Jeffrey; Barlogie, Bart; Bergsagel, Peter Leif; Kuehl, Michael.

In: Blood, Vol. 98, No. 1, 01.07.2001, p. 217-223.

Research output: Contribution to journalArticle

Shaughnessy, J, Gabrea, A, Qi, Y, Brents, L, Zhan, F, Tian, E, Sawyer, J, Barlogie, B, Bergsagel, PL & Kuehl, M 2001, 'Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma', Blood, vol. 98, no. 1, pp. 217-223. https://doi.org/10.1182/blood.V98.1.217
Shaughnessy, John ; Gabrea, Ana ; Qi, Ying ; Brents, Leslie ; Zhan, Fenghaung ; Tian, Erming ; Sawyer, Jeffrey ; Barlogie, Bart ; Bergsagel, Peter Leif ; Kuehl, Michael. / Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. In: Blood. 2001 ; Vol. 98, No. 1. pp. 217-223.
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abstract = "Reciprocal chromosomal translocations, which are mediated by errors in immunoglobulin heavy chain (IgH) switch recombination or somatic hypermutation as plasma cells are generated in germinal centers, are present in most multiple myeloma (MM) tumors. These translocations dysregulate an oncogene that is repositioned in proximity to a strong IgH enhancer. There is a promiscuous array of nonrandom chromosomal partners (and oncogenes), with the 3 most frequent partners (11q13 [cyclin D1]; 4p16 [FGFR3 and MMSET]; 16q23 [c-maf]) involved in nearly half of MM tumors. It is now shown that a novel t(6;14)(p21;q32) translocation is present in 1 of 30 MM cell lines and that this cell line uniquely overexpresses cyclin D3. The cloned breakpoint juxta-poses gamma 4 switch sequences with 6p21 sequences that are located about 65 kb centromeric to the cyclin D3 gene. By metaphase chromosome analysis, the t(6;14) (p21;q32) translocation was identified in 6 of 150 (4{\%}) primary MM tumors. Overexpression of cyclin D3 messenger RNA (mRNA) was identified by microarray RNA expression analysis in 3 of 53 additional primary MM tumors, each of which was found to have a t(6;14) translocation breakpoint by interphase fluorescence in situ hybridization analysis. One tumor has a t(6;22)(p21;q11) translocation, so that cyclin D3 is bracketed by the IgL and IgH breakpoints. These results provide the first clear evidence for primary dysregulation of cyclin D3 during tumorigenesis. It is suggested that the initial oncogenic event for most MM tumors is a primary immunoglobulin translocation that dysregulates cyclin D1, cyclin D3, and other oncogenes to provide a proliferative stimulus to postgerminal center plasma cells.",
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