The targeting of the sole cyclin D1 is not adequate for mantle cell lymphoma and myeloma therapies

Tchakarska, Guergana; Lan-Leguen, Anne Le; Roth, Lucile; Sola, Brigitte

doi:10.3324/haematol.2009.011460

Cited by 18 publications

(15 citation statements)

References 6 publications

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“…Because the 3 0 UTR length can be considered as a mechanism of gene expression regulation, we investigated if it can be involved in a potential cross-regulation between cyclin D1 and D2. It was previously observed in U266 cells, which express both cyclins D, that when cyclin D1 was silenced the level of cyclin D2 increased (19) and our results ascertain these data. Similar results have also been reported in MCL (32).…”

Section: Discussionsupporting

confidence: 82%

Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma

Misiewicz-Krzemińska

Sarasquete

Vicente-Dueñas

et al. 2016

Clinical Cancer Research

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Purpose: Dysregulation of one of the three D-cyclin genes has been observed in virtually all multiple myeloma tumors. The mechanisms by which CCND2 is upregulated in a set of multiple myeloma are not completely deciphered. We investigated the role of post-transcriptional regulation through the interaction between miRNAs and their binding sites at 3 0 UTR in CCND2 overexpression in multiple myeloma.Experimental Design: Eleven myeloma cell lines and 45 primary myeloma samples were included in the study. Interactions between miRNAs deregulated in multiple myeloma and mRNA targets were analyzed by 3 0 UTR-luciferase plasmid assay. The presence of CCND2 mRNA isoforms different in length was explored using qRT-PCR, Northern blot, mRNA FISH, and 3 0 rapid amplification of cDNA ends (RACE)-PCR.Results: We detected the presence of short CCND2 mRNA, both in the multiple myeloma cell lines and primary cells. The results obtained by 3 0 RACE experiments revealed that changes in CCND2 3 0 UTR length are explained by alternative polyadenylation. The luciferase assays using plasmids harboring the truncated CCND2 mRNA strongly confirmed the loss of miRNA sites in the shorter CCND2 mRNA isoform. Those multiple myelomas with greater abundance of the shorter 3 0 UTR isoform were associated with significant higher level of total CCND2 mRNA expression. Furthermore, functional analysis showed significant CCND2 mRNA shortening after CCND1 silencing and an increased relative expression of longer isoform after CCND1 and CCND3 overexpression, suggesting that cyclin D1 and D3 could regulate CCND2 levels through modifications in polyadenylation-cleavage reaction.Conclusions: Overall, these results highlight the impact of CCND2 3 0 UTR shortening on miRNA-dependent regulation of CCND2 in multiple myeloma.

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Section: Discussionsupporting

confidence: 82%

Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma

Misiewicz-Krzemińska

Sarasquete

Vicente-Dueñas

et al. 2016

Clinical Cancer Research

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“…It has been suggested that cyclin D1 production leads to the bypassing of the restriction point at the transition between the G1 and S phases, thus favoring uncontrolled proliferation. Consistent with this hypothesis, we and others have recently shown that cyclin D1 regulates the G1-S transition in MCL and MM cells (12,13). The contribution of other cyclin D1 functions to the oncogenic action of this protein in B cells remains to be determined.…”

Section: Introductionsupporting

confidence: 60%

Cyclin D1 Inhibits Mitochondrial Activity in B Cells

et al. 2011

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Cyclin D1 is a cell cycle regulatory protein that acts at the G1-S transition, following its binding to and activation by the cyclin-dependent kinases 4 or 6. Cyclin D1 is absent from the entire B-cell lineage but is present in a large percentage of 2 types of malignant B-cell hemopathy-mantle cell lymphoma and multiple myelomasuggesting a major role of this protein in the malignancy process. We show here, in an experimental model of cyclin D1 fusion protein transduction in mature B cells, that, cyclin D1 inhibits total mitochondrial activity. Cyclin D1 is localized at the outer mitochondrial membrane, bound to a voltage-dependent anion channel through its central domain, and it competes with hexokinase 2 for binding to this channel. The bound cyclin D1 decreases the supply of ADP, ATP, and metabolites, thereby reducing energy production. This function of cyclin D1 was also reported by others in normal and transformed mammary epithelial cells, suggesting that it may be ubiquitous. Cancer Res; 71(5);

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“…The relevance of selective cycD1 silencing in MCL has been questioned before due to compensatory elevation of cyclin D2 expression (35,36). In accordance with precedent reports, we detected that the down-regulation of cycD1 expression induces a compensatory up-regulation of cyclin D2 expression (Fig.…”

Section: Discussionsupporting

confidence: 81%

Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

Weinstein

Toker

Emmanuel

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Downregulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipidbased nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.nanomedicine | siRNA | mantle cell lymphoma | cyclin D1 | CD38

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The targeting of the sole cyclin D1 is not adequate for mantle cell lymphoma and myeloma therapies

Cited by 18 publications

References 6 publications

Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma

Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma

Cyclin D1 Inhibits Mitochondrial Activity in B Cells

Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

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