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CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Affymetrix]

ABSTRACT: Cyclin D1-negative mantle cell lymphomas (MCL) are not well characterized, in part due to the difficulties in their recognition. SOX11 has been recently identified as a reliable biomarker of MCL, also expressed in the cyclin D1-negative variant. We investigated 40 lymphomas with MCL morphology and immunophenotype, negative for cyclin D1 expression/t(11;14)(q13;q32) but SOX11-positive. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and had a poor outcome (5-year overall survival 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18/22 cases, in particular with light chains (10 IGK@, 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2 and CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1-negative SOX11-positive MCL analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11-positive MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome to the patients. This comprehensive characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the conventional cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42935 | GEO | 2012/12/19

SECONDARY ACCESSION(S): PRJNA183927

REPOSITORIES: GEO

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CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Agilent]

Project description:Cyclin D1-negative mantle cell lymphomas (MCL) are not well characterized, in part due to the difficulties in their recognition. SOX11 has been recently identified as a reliable biomarker of MCL, also expressed in the cyclin D1-negative variant. We investigated 40 lymphomas with MCL morphology and immunophenotype, negative for cyclin D1 expression/t(11;14)(q13;q32) but SOX11-positive. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and had a poor outcome (5-year overall survival 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18/22 cases, in particular with light chains (10 IGK@, 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2 and CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1-negative SOX11-positive MCL analyzed by copy number arrays were similar to the conventional cyclin D1/SOX11-positive MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome to the patients. This comprehensive characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the conventional cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients.

2012-12-19 | GSE42917 | GEO

CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Agilent]

2012-12-19 | E-GEOD-42917 | biostudies-arrayexpress

CCND2 rearrangements are the most frequent genetic events in Cyclin D1-negative mantle cell lymphoma [Affymetrix]

2012-12-19 | E-GEOD-42935 | biostudies-arrayexpress

A Novel Pro-Survival Function of Cyclin-D1 Underlies Its Oncogenic Role and Potential as a Therapeutic Target in Human and Murine Mantle Cell Lymphoma

Project description:The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 over-expression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current therapies. Cyclin-D1 has been postulated as an effective therapeutic target, but its evaluation has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model whereby cyclin-D1 expression can be externally regulated. These mice developed lymphomas capable of recapitulating most features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo. However, using a combination of in vitro and in vivo assays, we identified a novel pro-survival cyclin-D1 function in MCL cells. Specifically, we demonstrate that cyclin-D1 sequestrates the pro-apoptotic protein BAX, thereby favoring BCL2 anti-apoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a pro-apoptotic BH3 mimetic synergistically killed murine lymphomas and human MCL cells. Our study identifies a novel role of cyclin-D1 in deregulating apoptosis and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL.

2011-07-01 | GSE25613 | GEO

A Novel Pro-Survival Function of Cyclin-D1 Underlies Its Oncogenic Role and Potential as a Therapeutic Target in Human and Murine Mantle Cell Lymphoma

2011-07-01 | E-GEOD-25613 | biostudies-arrayexpress

Expression data from JVM13 cells with cyclin D1 exogenous overexpression

Project description:Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell cycle regulator and also has a role in transcription, but the effect of the latter in tumorigenesis remains largely unknown. Here, we investigated the transcriptional role of cyclin D1 in MCL and its impact on the pathogenesis of this neoplasm. Integrating genome-wide expression analysis of cyclin D1-silenced and overexpressing cells with cyclin D1 chromatin binding profiles, we identified a cyclin D1-activated transcriptional program in MCL cells. We used microarrays to analyze the genome-wide expression modulation in cyclin D1 overexpression models established in the cyclin D1-negative lymphoblastoid cell line JVM13.

2021-06-30 | GSE144095 | GEO

SOX11-positive and SOX11-knockdown xenograft derived tumor Gene Expression Profilings

Project description:The neural transcription factor SOX11 is overexpressed in aggressive lymphoid neoplasms mainly in mantle cell lymphoma (MCL). We have recently demonstrated SOX11 tumorigenic potential in vivo by showing a significant reduction on tumor growth of SOX11-knockdown MCL cells in xenograft experiments, confirming the clinical observations that SOX11 may play an important role in the aggressive behavior of MCL (Vegliante et al., 2013). However, the specific mechanisms regulated by SOX11 that promote the oncogenic and rapid tumor growth of aggressive MCL still remain to be elucidated. To further characterize the potential oncogenic mechanisms regulated by SOX11 in MCL, we have analyzed the GEP derived from the xenograft SOX11-positive and knockdown xenograft derived tumors. Differential gene expression between SOX11-positive Z138 and SOX11-negative Z138 MCL cell lines xenotransplanted in SCID mices derived tumors. To determine the transcriptional programs regulated by SOX11 we first generated a MCL cellular model with reduced SOX11 protein levels by infecting MCL cell lines with lentiviral particles carrying shRNA plasmids specifically targeting SOX11 (shSOX11.1 and shSOX11.3). Next, CB17-severe combined immunodeficient (CB17-SCID) mice (Charles River Laboratory, Wilmington, MA) were subcutaneously inoculated into their lower dorsum with Z138 shSOX11.1, shSOX11.3, shControl in Matrigel basement membrane matrix and compared the GEP of SOX11-positive and SOX11-negative MCL xenotransplant derived tumors using the Affymetrix U133+2.0 microarrays.

2014-11-04 | E-GEOD-52892 | biostudies-arrayexpress

SOX11-positive and SOX11-knockdown xenograft derived tumor Gene Expression Profilings

2014-11-04 | GSE52892 | GEO

RNA-sequencing in MCL cell lines after silencing cyclin D1

2021-06-30 | GSE144106 | GEO

Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice

Project description:We provide RNA sequencing data for a Ccnd2/p53/Mb1Cre mouse model (Mb1Cre is active from pre-B cells onwards). This mouse model features Ccnd2 overexpression and p53 loss in B-cells, and develops tumors that resembles Mantle cell lymphoma (MCL). These Ccnd2/p53/Mb1Cre mice develop both non-MCL and MCL-like lymphomas and RNA samples from both groups were sequenced. Fresh lymphoma cells (5x10exp6) were frozen in 700 µl of QIAZOL and stored in -80°C. RNA was prepared using a miRNeasy mini kit (Qiagen).

2021-08-10 | GSE175568 | GEO

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