Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells

Key Points Immune stimulation of cyclin D1 transgenic mice bearing Bim-deficient B cells induces an MCL phenotype. The induced lymphoma of EμCycD1CD19CREBimfl/fl mice highlights the collaborative roles of Bim deletion and cyclin D1 expression in MCL.

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Cyclin D1 Expression in Mantle Cell Lymphoma Is Accompanied by Downregulation of Cyclin D3 and Is Not Related to the Proliferative Activity

Blood ◽

10.1182/blood.v90.8.3154 ◽

1997 ◽

Vol 90 (8) ◽

pp. 3154-3159 ◽

Cited By ~ 42

Author(s):

M. Michaela Ott ◽

Jirina Bartkova ◽

Jiri Bartek ◽

Alexander Dürr ◽

Lars Fischer ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Chromosomal Translocation ◽

Germinal Centers ◽

Cyclin D3 ◽

Mantle Cell

Abstract The cell cycle regulatory protein cyclin D1 is essential for G1-S phase transition in several epithelial and mesenchymal tissues but is apparently not essential in normal mature B cells. An overexpression of cyclin D1 is induced by the chromosomal translocation t(11; 14)(q13; q32), which characterizes non-Hodgkin's lymphomas (NHLs) of mantle cell type. We studied 26 cases of mantle cell lymphoma (MCL) for the expression of cyclins D1 and D3. A total of 23 lymphomas showed a nuclear staining for cyclin D1, whereas reactive B cells of residual germinal centers were constantly negative. When compared with cyclin D3, an inverse staining pattern emerged. Whereas the B cells of residual germinal centers reacted strongly positive for cyclin D3, there was low or missing expression of cyclin D3 in MCL cells. In other B-cell lymphomas (n = 55), including chronic lymphocytic leukemia, low-grade lymphomas of mucosa-associated lymphatic tissue, follicular lymphomas, and diffuse large B-cell lymphomas, no cyclin D1 expression could be detected and 89% of these cases displayed cyclin D3 positivity. Lymphoma cell lines harboring the t(11; 14) showed cyclin D1 protein but no or very low levels of cyclin D3; three other B-cell lines, a T-cell line, and peripheral blood lymphocytes strongly expressed cyclin D3 and reacted negatively for cyclin D1. We conclude that the chromosomal translocation t(11; 14) leads to an abnormal protein expression of cyclin D1 in the tumor cells of MCL and induces a consecutive downregulation of cyclin D3. In contrast to other B-NHLs, cyclin D1 and D3 expression in MCL is not related to the growth fraction.

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Primary Cutaneous Mantle Cell Lymphoma: A Case Report

Case Reports in Dermatological Medicine ◽

10.1155/2013/394596 ◽

2013 ◽

Vol 2013 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

L. D. Mazzuoccolo ◽

G. A. Castro Perez ◽

I. Sorin ◽

A. I. Bravo

Keyword(s):

Radiation Therapy ◽

Case Report ◽

B Cells ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Therapeutic Options ◽

Molecular Characteristics ◽

Mantle Cell

Primary cutaneous mantle cell lymphoma (MCL) is a rare cutaneous proliferation of naive pregerminal CD-5 positive B cells in the skin with no extracutaneous involvement. Overexpression of cyclin D1 is pathognomonic of this condition, and surgery and radiation therapy are the most common therapeutic options. In this case, we describe the clinical, histopathological, immunohistochemical, and molecular characteristics of a new case of primary cutaneous MCL.

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CCND2 rearrangements are the most frequent genetic events in cyclin D1− mantle cell lymphoma

Blood ◽

10.1182/blood-2012-08-452284 ◽

2013 ◽

Vol 121 (8) ◽

pp. 1394-1402 ◽

Cited By ~ 106

Author(s):

Itziar Salaverria ◽

Cristina Royo ◽

Alejandra Carvajal-Cuenca ◽

Guillem Clot ◽

Alba Navarro ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Genetic Event ◽

Multidisciplinary Study ◽

Key Points ◽

Mantle Cell ◽

Genetic Events

Key Points This report describes a multidisciplinary study characterizing the largest series of cyclin D1− MCL patients. CCND2 translocations are the most frequent genetic event (55%) in cyclin D1− MCL.

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Characterization of a cryptic IGH/CCND1 rearrangement in a case of mantle cell lymphoma with negative CCND1 FISH studies

Blood Advances ◽

10.1182/bloodadvances.2019031450 ◽

2019 ◽

Vol 3 (8) ◽

pp. 1298-1302 ◽

Cited By ~ 5

Author(s):

Jess F. Peterson ◽

Linda B. Baughn ◽

Rhett P. Ketterling ◽

Beth A. Pitel ◽

Stephanie A. Smoley ◽

...

Keyword(s):

B Cell ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Mate Pair ◽

Key Points ◽

Mantle Cell

Key Points This article characterizes a cryptic IGH/CCND1 rearrangement in MCL by NGS. Mate-pair sequencing can help in accurately diagnosing MCL in cases of cyclin-D1–positive B-cell lymphoma with negative CCND1 FISH studies.

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Bortezomib Synergizes with a Novel Jak2 Inhibitor, WP-1130, To Inhibit Cell Growth and Induce Apoptosis in “Classic” and “Blastoid-Variant” Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.2512.2512 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2512-2512

Author(s):

Lan V. Pham ◽

Archito T. Tamayo ◽

Linda C. Yoshimura ◽

Waldeman Priebe ◽

Nicholas J. Donato ◽

...

Keyword(s):

B Cells ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Single Agent ◽

Therapeutic Agents ◽

Molecular Signature ◽

Drug Concentrations ◽

Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma B cells (NHL-B), a lymphoma with increasing incidence over the last few decades. MCLs are classified into at least two subgroups, “classic” type of MCL and “blastoid-variant”- an even more aggressive type of MCL. Both subgroups are incurable, unusually refractory to standard chemotherapy combinations and associated with poor prognosis. New therapeutic agents with greater efficacy and less toxicity are necessary in MCL. We have shown previously that in MCL cells, the key transcription factor NF-kB, is constitutively active and maintains lymphoma cells survival. We also demonstrated that treating the MCL cells with the proteasome inhibitor bortezomib (Velcade) inhibits constitutive NF-kB activation, leading to G1 cell cycle arrest and apoptosis. Recently, a novel small molecular weight compound called WP-1066, a derivative of AG490, was synthesized by screening a synthetic library for agents that block stat3 activation. WP-1066 has shown to have anti-tumor activity in MCL cells through the inhibition of IL-6 mediated stat3 activation and NF-kB inhibition. A more effective compound called WP-1130, a derivative of WP-1066, was synthesized and is shown to be more potent than WP-1066 in MCL cell lines. Single agents are rarely effective in treating a disease like MCL; therefore, we hypothesized that the combination of bortezomib and WP-1130 would likely be more effective in MCL. We showed that MCL cells, both “classic” and “blastoid-variant”, treated in-vitro with bortezomib in conjunction with WP-1130 resulted in a synergistic growth inhibition and apoptosis induction. The drug concentrations use for bortezomib and WP-1130 that produce the synergistic effects were in the low nanomolar (nM) and micromolar (uM) ranges, respectively. Bortezomib at a concentration of 10 nM induces approximately 15% MCL apoptosis after 48 hr treatment when compare to untreated controls, while WP-1130 at a concentration of 1 uM induces 5% apoptosis. The combination of bortezomib and WP-1130 at the same concentrations induces 60% of MCL cell apoptosis. Bortezomib and WP-1130 showed efficacy in both classic and blastoid-variant MCL cell lines. The apoptotic effects in these cells were correlated with the down-regulation of bcl-2 and the up-regulation of bax proteins. The status of constitutive NF-kB was also examined after drug treatments. While a single agent treatment with low drug concentrations had only minimal effect on NF-kB inhibition, the combination of the two drugs dramatically inhibits NF-kB activation. These two drugs also synergize to inhibit cyclin D1 (a molecular signature of MCL), and c-myc (an oncogene commonly over-expressed in lymphoma B cells). Agents such as bortezomib and WP-1130, that can pharmacologically modulate key intracellular targets such as constitutively expressed NF-kB and cyclin D1 in MCL cells, may be more effective therapeutic agents for the treatment of MCL.

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Transvection Mediated by the Translocated Cyclin D1 Gene in Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.4156.4156 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4156-4156

Author(s):

Elliot M. Epner ◽

Hui Liu ◽

Jing Wang ◽

Mathew Thayer

Keyword(s):

B Cells ◽

Somatic Cell ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Chromosome Translocations ◽

Mantle Cell ◽

G1 Cells ◽

Hybrid Fusion

Abstract Cyclin D1 expression in B cells is deregulated by chromosome translocations involving the immunoglobulin heavy chain (IgH) locus in mantle cell lymphoma (MCL). Gene targeting experiments produced MCL cell lines that had lost the translocated t(11;14) and no longer expressed cyclin D1. In these cyclin D1 (−) cells, the nonrearranged cyclin D1 (CCND1) locus reverts from CpG hypomethylated to hypermethylated. Reintroduction of the translocated chromosome by somatic cell hybrid fusion induces loss of methylation at the unrearranged CCND1 locus. Thus, the translocated chromosome exerts a transallelic effect on the unrearranged CCND1 locus in B cells that resembles transvection in Drosophilia. Control somatic cell fusion experiments with a nontranslocated cyclin D1 locus do not demonstrate transvection effects. We also have evidence for pairing of the translocated and nontranslocated cyclin D1 loci in MCL cell lines and MCL patient samples. This pairing is not related to DNA replication, as it is observed in flow sorted G1 cells and not in cyclin D1 expressing breast cancer cells or in B lymphocytes. In addition, to pairing of the cyclin D1 loci, we also have demonstrated translocation specific small RNAs in MCL cells upstream of the cyclin D1 gene.

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The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells

Blood ◽

10.1182/blood-2013-07-517177 ◽

2014 ◽

Vol 123 (19) ◽

pp. 2988-2996 ◽

Cited By ~ 132

Author(s):

Jenny Zhang ◽

Dereje Jima ◽

Andrea B. Moffitt ◽

Qingquan Liu ◽

Magdalena Czader ◽

...

Keyword(s):

B Cells ◽

Mantle Cell Lymphoma ◽

Burkitt Lymphoma ◽

Cell Lymphoma ◽

Chromatin State ◽

Genetic Mutations ◽

Genomic Landscape ◽

Cells Of Origin ◽

Key Points ◽

Mantle Cell

Key Points We identified novel recurrently mutated genes, including WHSC1, RB1, POT1, and SMARCA4, through exome sequencing of 56 cases of MCL. Genetic mutations defining MCL and Burkitt lymphoma were associated with the epigenetically defined chromatin state of their respective B cells of origin.

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Mantle Cell Lymphoma Associated Long Non-Coding RNAs Regulate Polycomb Repressive Complex-2

Blood ◽

10.1182/blood.v124.21.140.140 ◽

2014 ◽

Vol 124 (21) ◽

pp. 140-140 ◽

Cited By ~ 2

Author(s):

Guangzhen Hu ◽

Asha Nair ◽

Tammy Price-Troska ◽

Eric D Wieben ◽

Mamta Gupta

Keyword(s):

Cell Proliferation ◽

B Cells ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Cyclin D3 ◽

Polycomb Repressive Complex 2 ◽

Qrt Pcr ◽

Mantle Cell ◽

Non Coding Rnas

Abstract Long non-coding RNAs (lncRNA) are key regulatory RNAs that do not code for protein. Recently lncRNAs have been recognized as key regulators of gene expression and chromatin organization. Although, deregulation of lncRNAs such as HOTAIR, MALAT1 and H19 has been reported in solid cancers, role of lncRNAs in lymphoma or other hematologic malignancies is not known. The aim of this study is to identify lymphoma-associated lncRNAs and elucidate their role in disease pathogenesis. Next generation RNA-sequencing and validation studies were carried out on mantle cell lymphoma (MCL) patient samples along with normal controls. As a result, hundreds of lncRNAs were found overexpressed in the MCL samples as compared with normal B cells, including RP11-24J23.2 (50 fold), RP11-12A2.3 (36 fold) and DLEU7-AS1 (19 fold). Quantitative RT-PCR (QRT-PCR) confirmed higher expression of RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 in MCL patient samples as compared to normal B cells. To investigate the biological significance of lncRNAs in MCL cells, we overexpressed RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 lncRNAs and analyzed effects on cell proliferation and apoptosis. To achieve overexpression lncRNAs, RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 were cloned individually in expression pcDNA3.1 generating constructs: pcDNA3RP11-24J23.2, pcDNA3RP11-12A2.3 and pcDNA3DLEU7-AS1and then transfected into MCL cell lines along with pcDNA3.1. QRT-PCR revealed effective overexpression (~100 fold increase over baseline) for each transfected lncRNAs construct in Granta and Mino cells. Analysis of proliferation and survival showed that overexpressing RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1 promotes cell proliferation and survival in these cells as compared to the vector controls. Most of the lncRNAs found so far have been linked to the transcriptional regulation of the target genes through their association with chromatin remodeling factors such as Polycomb Repressive Complex 2 (PRC2). To identify the functional relevance of RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 lncRNAs, we examined the binding of the lymphoma specific lncRNAs with PRC2 complex, by performing RNA immunoprecipitation (RNA-IP) using specific antibodies to EZH2, EED and SUZ12. The RNA-IP results demonstrate high affinity binding of all three lncRNAs with SUZ12 and EED but a weak binding with EZH2. Furthermore, RNA-IP using antibody to histone 3-lysine 27 trimethylation (H3K27me3), a suppressive histone mark associated with PRC2 complex, also showed efficient binding with RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1. These results suggest that RP11-24J23.2, RP11-12A2.3, and DLEU7-AS1 lncRNAs can directly associated with PRC2 complex at chromatin. To understand the mechanism of increased cell growth after overexpression of lncRNAs, RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1, we analyzed expression level of important genes signature of MCL pathogenesis that include cyclin D1, cyclin D3, c-Myc, P14, and SOX11, a member of the group C SOX (SRY-related HMG-box) transcription factor family. Our results demonstrate that overexpression of lncRNAs RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1 enhanced the levels of cyclin D1 (>2 fold) mRNA without any impact on cyclin D3 or c-Myc transcript levels. In contrast overexpression of RP11-24J23.2, RP11-12A2.3 or DLEU7-AS1 lncRNAs decreased SOX11 (0.08, 0.1 and 0.06 respectively) and P14 (0.06, 0.7 and 0.40 respectively) mRNA expression in Mino cells. To gain understanding of the mechanism involved in the suppression of SOX11 by the lncRNAs, we performed Chromatin immunoprecipitation assays with EZH2, EED and SUZ12 antibodies on Mino cells transfected with pcDNA3RP11-24J23.2, pcDNA3RP11-12A2.3 and pcDNA3DLEU7-AS1 or vector control. The data showed that overexpression of RP11-12A2.3 and DLEU7-AS1 significantly increased the binding of EED and to a lesser extent of EZH2 to SOX11 promoter while the binding of SUZ12 to SOX11 promoter was not changed as compared to vector alone. In conclusion, our results imply that lncRNAs are overexpressed in the MCL. Moreover, lymphoma associated lncRNAs (RP11-24J23.2, RP11-12A2.3 and DLEU7-AS1) regulate SOX11 expression via PRC2 complex contributing towards growth of MCL cells. Specific nature of lncRNAs found in lymphoma samples suggests that lncRNAs can be used as potential biomarkers for mantle cell lymphoma. Disclosures No relevant conflicts of interest to declare.

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A147 PRIMARY COLONIC MANTLE CELL LYMPHOMA: A RARE ENTITY

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.145 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 138-140

Author(s):

K Donaldson ◽

S Nassiri ◽

D Chahal ◽

M F Byrne

Keyword(s):

Case Report ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Transverse Colon ◽

Cell Lymphoma ◽

Rapid Progression ◽

Rare Entity ◽

Gi Bleeding ◽

Gi Tract ◽

Mantle Cell

Abstract Background Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL), often diagnosed at later stages with secondary gastrointestinal (GI) involvement. Primary GI MCL is rare and is not often discussed in the literature. Aims To increase awareness of a rare condition that is likely to be encountered but can be challenging to diagnose. Methods Case report and review of the literature. Results Case Report A 78-year-old man with multiple untreated vascular risk factors including atrial fibrillation and type 2 diabetes presented with acute onset left hemiplegia, dysarthria, and imaging consistent with a left pontine stroke. As part of his workup he underwent a CT abdomen/pelvis identifying an 11 x 5 cm intraluminal mass in the transverse colon. Previous screening colonoscopies, for family history of colon cancer, were notable for tubular adenomas without high-grade dysplasia at 13, 12, 10, 7, and 2 years prior to admission. The patient had 16 pounds of weight loss without other constitutional symptoms, change in bowel habits or evidence of GI bleeding. Bloodwork was notable for microcytic anemia (Hemoglobin 91 g/L, MCV 75 fL), from a normal baseline one year prior, without other cytopenias. C-reactive protein (44 mg/L) and GGT (164 U/L) were elevated. Other liver enzymes, lactate dehydrogenase, and electrolytes were normal. Colonoscopy revealed numerous polypoid lesions throughout the entire colon and a large non-obstructive mass with submucosal appearance in the transverse colon. Biopsies were taken from the large mass and one of the smaller polypoid lesions. Histology showed a sheet-like infiltrate of small lymphocytes within the lamina propria. Immunohistochemical staining was positive for CD20, BCL2, Cyclin D1, equivocal for CD5, and negative for BCL6 and CD3. Ki67 index approached 30%. A diagnosis of colonic MCL was made. Literature Review Primary MCL of the GI tract is rare, accounting for only 1 to 4% of all GI malignancies. There is a male and Caucasian predominance with a median age of 68 years at diagnosis. Presenting complaints may include abdominal pain, anorexia, and GI bleeding. Typical endoscopic features are small nodular or polypoid tumors, between 2mm and 2 cm in size, along one or more segments of the GI tract referred to as multiple lymphomatous polyposis (MLP). A single colonic mass is infrequently seen, highlighting the importance of endoscopy for diagnosis, as subtle findings may be missed on radiographic evaluation. Biopsies for immunohistochemistry are essential to distinguish MCL from other NHLs, as almost all cases express cyclin D1. Despite aggressive immunochemotherapy, prognosis is often poor due to MCL’s rapid progression and early relapse. Conclusions Primary GI MCL is a rare entity. Awareness is essential as evaluation and management differ from lymphoma at other sites, and other GI malignancies. Funding Agencies None

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Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)

Blood ◽

10.1182/blood-2013-08-523845 ◽

2014 ◽

Vol 123 (11) ◽

pp. 1665-1673 ◽

Cited By ~ 43

Author(s):

Julie E. Chang ◽

Hailun Li ◽

Mitchell R. Smith ◽

Randy D. Gascoyne ◽

Elisabeth M. Paietta ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Eastern Cooperative Oncology Group ◽

Phase 2 ◽

Oncology Group ◽

Oncology Group Study ◽

Phase 2 Study ◽

Key Points ◽

Mantle Cell

Key Points VcR-CVAD produced high overall and CR rates in previously untreated MCL patients. No substantial difference in 3-year PFS or OS was observed in patients receiving ASCT compared with patients receiving maintenance rituximab.

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