Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA732916 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14660555.fastq.gz | Fastqsanger.gz | |||
| SRR14660556.fastq.gz | Fastqsanger.gz | |||
| SRR14660557.fastq.gz | Fastqsanger.gz | |||
| SRR14660558.fastq.gz | Fastqsanger.gz | |||
| SRR14660559.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that hematopoiesis-specific activation of cyclin D2 is sufficient to drive murine MCL-like lymphoma development. Furthermore, we demonstrate that cyclin D2 overexpression can synergize with loss of p53 to form aggressive and transplantable MCL-like lymphomas. Strikingly, cyclin D2-driven lymphomas display transcriptional, immunophenotypic, and functional similarities with B1a B cells. These MCL-like lymphomas have B1a-specific B cell receptors (BCRs), show elevated BCR and NF-κB pathway activation, and display increased MALT1 protease activity. Finally, we provide preclinical evidence that inhibition of MALT1 protease activity, which is essential for the development of early life-derived B1a cells, can be an effective therapeutic strategy to treat MCL.
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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.
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Project description:Mantle cell lymphoma (MCL) is a B cell malignancy characterized by a monoclonal proliferation of lymphocytes with co-expression of CD5, CD43 but not CD23. Typical MCL are associated with cyclin D1 overexpression, and blastoid MCL variants are associated with c-myc translocations. We have developed a murine model of MCL-like lymphoma by crossing Cdk4R24C mice with c-myc-3’RR transgenic mice. Cdk4R24C mice is a knock-in strain that express a Cdk4 protein resistant to inhibition by p16INK4a and other INK4 family members. Breeding Cdk4R24C mice with c-myc-3’RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma leads in c-myc/Cdk4R24C mice to development of clonal blastoid MCL-like lymphoma. A defect of the INK4-Cdk4 checkpoint can participate to lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation which might be reminiscent of the development of human blastoid MCL. B splenocytes from 4 c-myc/Cdk4(R24C) lymphoma mice and 4 wt mice were investigated.
2012-02-01 | E-GEOD-32230 | biostudies-arrayexpress
Project description:Mantle cell lymphoma (MCL) is a B cell malignancy characterized by a monoclonal proliferation of lymphocytes with co-expression of CD5, CD43 but not CD23. Typical MCL are associated with cyclin D1 overexpression, and blastoid MCL variants are associated with c-myc translocations. We have developed a murine model of MCL-like lymphoma by crossing Cdk4R24C mice with c-myc-3’RR transgenic mice. Cdk4R24C mice is a knock-in strain that express a Cdk4 protein resistant to inhibition by p16INK4a and other INK4 family members. Breeding Cdk4R24C mice with c-myc-3’RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma leads in c-myc/Cdk4R24C mice to development of clonal blastoid MCL-like lymphoma. A defect of the INK4-Cdk4 checkpoint can participate to lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation which might be reminiscent of the development of human blastoid MCL.
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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
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.
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Project description:In this study we could show that the treatment of primary murine prostate cancer(PCa) cells derived from the well-established TRAMP (transgenic adenocarcinoma ofmouse prostate) model with the histone deacetylase inhibitor (HDI) valproic acid (VPA) has an anti-proliferative, anti-migrative and anti-invasive effect on the cells.To our knowledge this is the first study that identified that treatment of PCa cells with VPA leads to the re-expression of cyclin D2, which is known to be frequently inactive in patients with PCa. Additionally, we could demonstrate that VPA specifically induces re-expression of cyclin D2 as a family member of the highly conserved Dtype cyclins in human colorectal and mammary gland adenocarcinoma cell lines, whereas VPA treatment has no effect in NIH/3T3 fibroblasts. The observed cyclin D2 re-expression in cancer cells is activated by an increase of histone acetylation in the promoter region of the cyclin D2 gene and might be the underlying molecular mechanism of the inhibition of proliferation of cancer cells after VPA treatment. Taken together, our results confirm VPA as an anticancer therapeutic option in tumors with epigenetically repressed cyclin D2 expression. For the comparison of vpa treatment in murine protate cancer cells we hybridized 3 replicates per condition
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