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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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE25613 | GEO | 2011/07/01

SECONDARY ACCESSION(S): PRJNA134267

REPOSITORIES: GEO

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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. Dose response involving 20 samples. Two replicates for each cell line, 4 cell lines sensitive to ABT-737 and 6 cell lines resistant to ABT-737. Mantel cell lymphoma cell lines sensitive to ABT-737 vs. Mantel cell lymphoma cell lines resistant to ABT-737

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

RNA-sequencing in MCL cell lines after silencing cyclin D1

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.

2021-06-30 | GSE144106 | GEO

Expression data from JVM13 cells with cyclin D1 exogenous overexpression

2021-06-30 | GSE144095 | GEO

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

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 | GSE42935 | GEO

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

2012-12-19 | GSE42917 | GEO

The Gene Expression Study (GEP) was based on a 6 MCL cell line models.

Project description:The aggressive clinical behavior of mantle cell lymphoma (MCL) is attributed to specific genetic and molecular mechanisms involved in its pathogenesis, mainly the t(11;14)(q13;q32) traslocation and cyclin D1 (CCND1) overexpression. Nevertheless, evidence of a certain degree of heterogeneity has been disclosed by gene expression profile (GEP) and (immuno)genetic/immunohistochemistry studies. AIM: To use a GEP approach in MCL cell line models.

2017-12-31 | GSE89615 | 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

The Gene Expression Study (GEP) was based on a cohort of 27 MCL cases enrolled in the Fondazione Italiana Linfomi (FIL)-MCL-0208 randomized Italian clinical trial.

Project description:The aggressive clinical behavior of mantle cell lymphoma (MCL) is attributed to specific genetic and molecular mechanisms involved in its pathogenesis, mainly the t(11;14)(q13;q32) traslocation and cyclin D1 (CCND1) overexpression. Nevertheless, evidence of a certain degree of clinical/biological heterogeneity has been disclosed by gene expression profile (GEP) and (immuno)genetic/immunohistochemistry studies. AIM: To use a GEP approach to identify MCL subsets with peculiar clinical/biological features in the context of of MCL patients treated homogeneously with an autologous transplantation-based program.

2017-12-31 | GSE89447 | GEO

Expression data from MALD1 and MCL cases

Project description:Patients with conventional mantle cell lymphoma (MCL) show an aggressive clinical behavior. However, cases fulfilling the WHO criteria for MCL, but that remain asymptomatic without treatment, have been reported. In an attempt to understand this heterogeneity, we have compared 17 typical cases of MCL with a homogeneous group of 13 asymptomatic individuals with monoclonal expansion of t(11;14)(q13;q32) cyclin D1-positive B-cells in peripheral blood (MALD1). None of these cases have received treatment (minimum follow-up of 26 months; median, 71 months). Gene expression analysis has shown enrichment of signatures associated to neoplastic behavior and cell proliferation in MCL but not in MALD1. In contrast, MALD1 was highly enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 genes were differentially expressed between MCL and MALD1. The combined assessment of both proteins by flow cytometry allowed classifying 85% of MALD1 cases. In summary, we have shown for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. We have also shown that CD38 and CD200 flow cytometry assessment is useful to discern most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment. 18 samples were analyzed: 5 MALD1, 5 MCL and 8 Healthy Controls

2013-12-23 | E-GEOD-45717 | biostudies-arrayexpress

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