RNA Inhibition Highlights Cyclin D1 as a Potential Therapeutic Target for Mantle Cell Lymphoma

Weinstein, Shiri; Emmanuel, Rafi; Jacobi, Ashley M.; Avigdor, Abraham; Behlke, Mark A.; Sprague, Andrew; Novobrantseva, Tatiana; Nagler, Arnon; Peer, Dan

doi:10.1371/journal.pone.0043343

Cited by 25 publications

(30 citation statements)

References 17 publications

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“…In contrast, Weinstein et al . detected apoptosis in the GRANTA-519 and JEKO-1 lines eight days after CCND1 siRNA transfection [31]. In agreement with the study of Weinstein et al .…”

Section: Discussionsupporting

confidence: 82%

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Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines

Mohanty¹,

Mohanty²,

Sandoval³

et al. 2016

Leukemia & Lymphoma

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Elevated cyclin D1 (CCND1) expression levels in mantle cell lymphoma (MCL) are associated with aggressive clinical manifestations related to chemoresistance, but little is known about how this important proto-oncogene contributes to the resistance of MCL. Here, we showed that RNA interference-mediated depletion of CCND1 increased caspase-3 activities and induced apoptosis in the human MCL lines UPN-1 and JEKO-1. In vitro and xenotransplant studies revealed that the toxic effect of CCND1 depletion in MCL cells was likely due to increase in histone H2AX phosphorylation, a DNA damage marker. DNA fiber analysis suggested deregulated replication initiation after CCND1 depletion as a potential cause of DNA damage. Finally, in contrast to depletion or inhibition of cyclin-dependent kinase 4, CCND1 depletion increased chemosensitivity of MCL cells to replication inhibitors hydroxyurea and cytarabine. Our findings have an important implication for CCND1 as a potential therapeutic target in MCL patients who are refractory to standard chemotherapy.

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“…In contrast, Weinstein et al . detected apoptosis in the GRANTA-519 and JEKO-1 lines eight days after CCND1 siRNA transfection [31]. In agreement with the study of Weinstein et al .…”

Section: Discussionsupporting

confidence: 82%

“…In agreement with the study of Weinstein et al . [31], our data indicate that CCND1 is essential in JEKO-1 (and UPN-1) cells. Apoptosis in JEKO-1 cells after CCND1 depletion was detected both in the Weinstein et al .…”

Section: Discussionmentioning

confidence: 66%

Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines

Mohanty¹,

Mohanty²,

Sandoval³

et al. 2016

Leukemia & Lymphoma

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“…This raise the future possibility of purifying MCL derived exosomes from patient’s serum and harnessing them for the delivery of therapeutic payloads while exploiting their natural specifically towards MCL cells. Since exosomes could be taken up by monocytes as well, exosomes might be loaded with specific anti MCL molecules, such as siRNA molecules for cyclin D1, which was previously shown by us to decrease viability of MCL cells and induced cell apoptosis[48]. …”

Section: Discussionmentioning

confidence: 99%

Cell-specific uptake of mantle cell lymphoma-derived exosomes by malignant and non-malignant B-lymphocytes

et al. 2015

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Mantle cell lymphoma (MCL) is an aggressive and incurable mature B cell neoplasm. The current treatments are based on chemotherapeutics and new class of drugs (e.g. Ibrutinib®), which in most cases ends with tumor resistance and relapse. Therefore, further development of novel therapeutic modalities are needed. Exosomes are natural extracellular vesicles, which play an important role in intercellular communication. The specificity of exosome uptake by different target cells remains unknown. In this study, we observed that MCL exosomes are taken up rapidly and preferentially by MCL cells. Only minor fraction of exosomes was internalized into T-cell leukemia and bone marrow stroma cell lines, when these cells were co-cultured with MCL cells. Moreover, MCL patients’ exosomes were taken up by both healthy and patients’ B-lymphocytes with no apparent internalization to T lymphocytes and NK cells. Exosome internalization was not inhibited by specific siRNA against caveolin1 and clathrin but was found to be mediated by cholesterol-dependent pathway. These findings demonstrate natural specificity of exosomes to B-lymphocytes and ultimately might be used for therapeutic intervention in B cells malignancies.

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“…In the in vivo studies, we did not succeed in demonstrating gene silencing in a direct manner. However, former studies performed in vitro demonstrated that the silencing of cycD1 induces cell cycle arrest and cell death (9). These findings imply there should be a "selective force" against the targeted cells in which cycD1 was knocked down, interfering with the ability to detect the silencing of cycD1 in the BM of tumor-bearing mice.…”

Section: Discussionmentioning

confidence: 97%

“…We previously showed that cycD1 down-regulation in MCL cell lines using RNAi inhibits proliferation and causes cell cycle arrest and apoptosis (9). However, the clinical application of this approach is hindered by the lack of appropriate systems that could deliver RNAi payloads to MCL cells in an efficient and safe manner (10,11).…”

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confidence: 99%

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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RNA Inhibition Highlights Cyclin D1 as a Potential Therapeutic Target for Mantle Cell Lymphoma

Cited by 25 publications

References 17 publications

Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines

Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines

Cell-specific uptake of mantle cell lymphoma-derived exosomes by malignant and non-malignant B-lymphocytes

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

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