Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival

Adrian Wiestner, Mahsa Tehrani, Michael Chiorazzi, George Wright, Federica Gibellini, Kazutaka Nakayama, Hui Liu, Andreas Rosenwald, H. Konrad Muller-Hermelink, German Ott, Wing C. Chan, Timothy C. Greiner, Dennis D. Weisenburger, Julie Vose, James O. Armitage, Randy D. Gascoyne, Joseph M. Connors, Elias Campo, Emilio Montserrat, Francesc BoschErlend B. Smeland, Stein Kvaloy, Harald Holte, Jan Delabie, Richard I. Fisher, Thomas M. Grogan, Thomas P Miller, Wyndham H. Wilson, Elaine S. Jaffe, Louis M. Staudt

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated 3′UTRs, not alternatively spliced cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated cyclin D1 mRNAs, 7 had genomic deletions in the CCND1 3′UTR region. In 3 others, CCND1 contained point mutations that created premature polyadenylation signals, giving rise to 1.5-kb mRNAs lacking most of the 3′UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type cyclin D1a mRNA. Premature polyadenylation due to a 3′UTR mutation also was present in the Z-138 MCL cell line, which expressed both truncated and full-length cyclin D1a mRNAs. In these cells, the half-life of the short cyclin D1a mRNA was much longer than that of the full-length mRNA. We conclude that alterations of CCND1 3′UTR structure can significantly increase its oncogenic effect and worsen the clinical course of MCL patients.

Original languageEnglish (US)
Pages (from-to)4599-4606
Number of pages8
JournalBlood
Volume109
Issue number11
DOIs
StatePublished - Jun 1 2007
Externally publishedYes

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Cyclin D1
Point Mutation
Survival Rate
Mantle-Cell Lymphoma
Cyclins
Messenger RNA
RNA Isoforms
Tumors
Polyadenylation
Neoplasms
Transcriptome
Gene expression
Half-Life
Protein Isoforms
Cells
Cell Line
Mutation
Survival

ASJC Scopus subject areas

  • Hematology

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Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. / Wiestner, Adrian; Tehrani, Mahsa; Chiorazzi, Michael; Wright, George; Gibellini, Federica; Nakayama, Kazutaka; Liu, Hui; Rosenwald, Andreas; Muller-Hermelink, H. Konrad; Ott, German; Chan, Wing C.; Greiner, Timothy C.; Weisenburger, Dennis D.; Vose, Julie; Armitage, James O.; Gascoyne, Randy D.; Connors, Joseph M.; Campo, Elias; Montserrat, Emilio; Bosch, Francesc; Smeland, Erlend B.; Kvaloy, Stein; Holte, Harald; Delabie, Jan; Fisher, Richard I.; Grogan, Thomas M.; Miller, Thomas P; Wilson, Wyndham H.; Jaffe, Elaine S.; Staudt, Louis M.

In: Blood, Vol. 109, No. 11, 01.06.2007, p. 4599-4606.

Research output: Contribution to journalArticle

Wiestner, A, Tehrani, M, Chiorazzi, M, Wright, G, Gibellini, F, Nakayama, K, Liu, H, Rosenwald, A, Muller-Hermelink, HK, Ott, G, Chan, WC, Greiner, TC, Weisenburger, DD, Vose, J, Armitage, JO, Gascoyne, RD, Connors, JM, Campo, E, Montserrat, E, Bosch, F, Smeland, EB, Kvaloy, S, Holte, H, Delabie, J, Fisher, RI, Grogan, TM, Miller, TP, Wilson, WH, Jaffe, ES & Staudt, LM 2007, 'Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival', Blood, vol. 109, no. 11, pp. 4599-4606. https://doi.org/10.1182/blood-2006-08-039859
Wiestner, Adrian ; Tehrani, Mahsa ; Chiorazzi, Michael ; Wright, George ; Gibellini, Federica ; Nakayama, Kazutaka ; Liu, Hui ; Rosenwald, Andreas ; Muller-Hermelink, H. Konrad ; Ott, German ; Chan, Wing C. ; Greiner, Timothy C. ; Weisenburger, Dennis D. ; Vose, Julie ; Armitage, James O. ; Gascoyne, Randy D. ; Connors, Joseph M. ; Campo, Elias ; Montserrat, Emilio ; Bosch, Francesc ; Smeland, Erlend B. ; Kvaloy, Stein ; Holte, Harald ; Delabie, Jan ; Fisher, Richard I. ; Grogan, Thomas M. ; Miller, Thomas P ; Wilson, Wyndham H. ; Jaffe, Elaine S. ; Staudt, Louis M. / Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. In: Blood. 2007 ; Vol. 109, No. 11. pp. 4599-4606.
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abstract = "A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated 3′UTRs, not alternatively spliced cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated cyclin D1 mRNAs, 7 had genomic deletions in the CCND1 3′UTR region. In 3 others, CCND1 contained point mutations that created premature polyadenylation signals, giving rise to 1.5-kb mRNAs lacking most of the 3′UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type cyclin D1a mRNA. Premature polyadenylation due to a 3′UTR mutation also was present in the Z-138 MCL cell line, which expressed both truncated and full-length cyclin D1a mRNAs. In these cells, the half-life of the short cyclin D1a mRNA was much longer than that of the full-length mRNA. We conclude that alterations of CCND1 3′UTR structure can significantly increase its oncogenic effect and worsen the clinical course of MCL patients.",
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T1 - Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival

AU - Wiestner, Adrian

AU - Tehrani, Mahsa

AU - Chiorazzi, Michael

AU - Wright, George

AU - Gibellini, Federica

AU - Nakayama, Kazutaka

AU - Liu, Hui

AU - Rosenwald, Andreas

AU - Muller-Hermelink, H. Konrad

AU - Ott, German

AU - Chan, Wing C.

AU - Greiner, Timothy C.

AU - Weisenburger, Dennis D.

AU - Vose, Julie

AU - Armitage, James O.

AU - Gascoyne, Randy D.

AU - Connors, Joseph M.

AU - Campo, Elias

AU - Montserrat, Emilio

AU - Bosch, Francesc

AU - Smeland, Erlend B.

AU - Kvaloy, Stein

AU - Holte, Harald

AU - Delabie, Jan

AU - Fisher, Richard I.

AU - Grogan, Thomas M.

AU - Miller, Thomas P

AU - Wilson, Wyndham H.

AU - Jaffe, Elaine S.

AU - Staudt, Louis M.

PY - 2007/6/1

Y1 - 2007/6/1

N2 - A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated 3′UTRs, not alternatively spliced cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated cyclin D1 mRNAs, 7 had genomic deletions in the CCND1 3′UTR region. In 3 others, CCND1 contained point mutations that created premature polyadenylation signals, giving rise to 1.5-kb mRNAs lacking most of the 3′UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type cyclin D1a mRNA. Premature polyadenylation due to a 3′UTR mutation also was present in the Z-138 MCL cell line, which expressed both truncated and full-length cyclin D1a mRNAs. In these cells, the half-life of the short cyclin D1a mRNA was much longer than that of the full-length mRNA. We conclude that alterations of CCND1 3′UTR structure can significantly increase its oncogenic effect and worsen the clinical course of MCL patients.

AB - A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated 3′UTRs, not alternatively spliced cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated cyclin D1 mRNAs, 7 had genomic deletions in the CCND1 3′UTR region. In 3 others, CCND1 contained point mutations that created premature polyadenylation signals, giving rise to 1.5-kb mRNAs lacking most of the 3′UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type cyclin D1a mRNA. Premature polyadenylation due to a 3′UTR mutation also was present in the Z-138 MCL cell line, which expressed both truncated and full-length cyclin D1a mRNAs. In these cells, the half-life of the short cyclin D1a mRNA was much longer than that of the full-length mRNA. We conclude that alterations of CCND1 3′UTR structure can significantly increase its oncogenic effect and worsen the clinical course of MCL patients.

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