Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

AbstractMantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma of which at least a subset arises from antigen-experienced B cells. However, what role antigen stimulation plays in its pathogenesis remains ill defined. The genetic hallmark is the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. Secondary genetic events increase the oncogenic potential of cyclin D1 and frequently inactivate DNA damage response pathways. In combination these changes drive cell-cycle progression and give rise to pronounced genetic instability. Several signaling pathways contribute to MCL pathogenesis, including the often constitutively activated PI3K/AKT/mTOR pathway, which promotes tumor proliferation and survival. WNT, Hedgehog, and NF-κB pathways also appear to be important. Although MCL typically responds to frontline chemotherapy, it remains incurable with standard approaches. Proteasome inhibitors (bortezomib), mTOR inhibitors (temsirolimus), and immunomodulatory drugs (lenalidomide) have recently been added to the treatment options in MCL. The molecular basis for the antitumor activity of these agents is an area of intense study that hopefully will lead to further improvements in the near future. Given its unique biology, relative rarity, and the difficulty in achieving long-lasting remissions with conventional approaches, patients with MCL should be encouraged to participate in clinical trials.

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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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A Novel Pro-Survival Function of Cyclin-D1 Underlies Its Oncogenic Role and Potential as a Therapeutic Target In Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v116.21.769.769 ◽

2010 ◽

Vol 116 (21) ◽

pp. 769-769

Author(s):

Elena Beltran ◽

Vicente Fresquet ◽

Javier Martinez-Useros ◽

Jose A. Richter-Larrea ◽

Ainara Sagardoy ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Survival Function ◽

Chromosomal Translocation ◽

Molecular Features ◽

Oncogenic Pathways ◽

Mantle Cell

Abstract Abstract 769 Despite the many and diverse therapeutic approaches used to treat patients with mantle cell lymphoma (MCL), it remains an incurable disease. Recently, attention has turned into novel therapies targeting MCL-specific oncogenic pathways important for the growth and maintenance of the transformed phenotype. The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 over-expression is the hallmark of MCL. Constitute cyclin-D1 activation in B-lymphocytes maintains retinoblastoma protein in a phosphorylated state and promotes cell cycling, thus initiating the tumorigenesis process. Cyclin-D1 has been postulated as a putative target for therapeutic intervention, however its evaluation has been hampered by the incomplete understanding of the mechanism underlying this cyclin oncogenic function and by the lack of valid MCL models. To investigate these issues, we developed a combined cellular-genomics screening whereby responses to known cytotoxic compounds targeting cancer-related molecular pathways were correlated with genomic, gene expression and proteomic profiles of human MCL cells. Results showed that cyclin-D1 silencing had minimal antitumoral effects but significantly increased the therapeutic efficacy of several compounds, especially the BH3 mimetics that inhibited anti-apoptotic protein BCL-2. To further evaluate this finding we generated a MCL mouse model by transducing a tetracycline-regulatable cyclin-D1-expressing vector in murine pro-B cells, which allowed modulating cyclin-D1 expression levels. These mice generated lymphomas recapitulating most of the cellular, histopathological and molecular features of human MCL. Similar to the previous in vitro findings, cyclin-D1 inhibition in this model did not induce lymphoma regression, but sensitized cells to apoptosis. Analysis of the mechanisms underlying this therapeutic synergy identified a novel role for cyclin-D1 as a pro-survival molecule. Specifically, cyclin-D1 sequestrated the pro-apoptotic effector protein BAX in MCL cells, thereby favoring BCL2 anti-apoptotic function. Accordingly, therapeutic cyclin-D1 inactivation released BAX, thus sensitizing cells to apoptosis and inducing lymphoma regression. Interestingly, pharmacological blockade in vivo of cyclin-D1 with Roscovitine synergistically cooperated with the BH3 mimetic ABT-737 to effectively inhibit MCL tumor growth. In summary, our study reveals a novel role for cyclin-D1 in deregulating apoptosis in MCL cells and highlights the potential benefit of cyclin-D1 targeting, thus providing the rationale for the clinical evaluation of drugs targeting cell proliferation and survival pathways in MCL. Disclosures: Siebert: Abbott: Honoraria.

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A chromosomal translocation in cyclin D1–negative/cyclin D2–positive mantle cell lymphoma fuses the CCND2 gene to the IGK locus

Blood ◽

10.1182/blood-2006-01-0015 ◽

2006 ◽

Vol 108 (3) ◽

pp. 1109-1110 ◽

Cited By ~ 61

Author(s):

Stefan Gesk ◽

Wolfram Klapper ◽

José I. Martín-Subero ◽

Inga Nagel ◽

Lana Harder ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Chromosomal Translocation ◽

Cyclin D2 ◽

Mantle Cell

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A Rare Manifestation of a Rare Disease: Mantle Cell Lymphoma Presenting With Aseptic Meningitis

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709619858643 ◽

2019 ◽

Vol 7 ◽

pp. 232470961985864

Author(s):

Elvira Umyarova ◽

Sreedhar Adapa ◽

Srikanth Naramala ◽

Vijay Gayam ◽

Narothama Reddy Aeddula ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Aseptic Meningitis ◽

Cell Lymphoma ◽

Chromosomal Translocation ◽

Aberrant Expression ◽

Non Hodgkin Lymphoma ◽

Clonal Proliferation ◽

Mantle Cell ◽

Short Overall Survival ◽

Apoptotic Pathways

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin lymphoma characterized by clonal proliferation of follicular mantle zone B lymphocytes. It is caused by abnormal chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. This leads to activation of anti-apoptotic pathways and abnormal proliferation of MCL cells. Patients can present with an indolent course or a fulminant disease with short overall survival. The disease frequently involves extranodal organs, but rarely manifests with neurological symptoms. We report a rare case of aberrant CD5-negative MCL presenting with aseptic meningitis.

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Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity

Blood ◽

10.1182/blood-2006-04-016634 ◽

2006 ◽

Vol 108 (5) ◽

pp. 1744-1750 ◽

Cited By ~ 87

Author(s):

Michal Marzec ◽

Monika Kasprzycka ◽

Raymond Lai ◽

Andrew B. Gladden ◽

Pawel Wlodarski ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Cycle Progression ◽

Cell Lymphoma ◽

Constitutive Expression ◽

Selective Inhibition ◽

Tissue Samples ◽

Mantle Cell ◽

Rb Phosphorylation

The prognosis for patients with mantle cell lymphoma (MCL) is poor, and at present there is no truly effective therapy. Gene translocation-mediated constitutive expression of cyclin D1 seems to play the key role in the pathogenesis of MCL. Here we report that although 3 of 4 MCL cell lines expressed the recently identified, highly oncogenic cyclin D1b isoform, as well as the canonical cyclin D1a, 8 MCL patient samples expressed only the cyclin D1a protein despite expressing detectable cyclin D1b mRNA. Cell lines and tissue samples displayed constitutive activation of the cyclin D1 signaling cascade, as evidenced by strong expression of CDK4, Rb phosphorylation, and cyclin D1/CDK4 coassociation. All MCL cell lines and tissues examined displayed nondetectable to diminished expression of the cyclin D1 inhibitor p16. Novel small molecule CDK4/CDK6 inhibitor PD0332991 profoundly suppressed—at low nanomolar concentrations—Rb phosphorylation, proliferation, and cell cycle progression at the G0/G1 phase of MCL cells. These findings provide evidence that MCL should be very sensitive to targeted therapy aimed at functional inhibition of the cyclin D1/CDK4 complex.

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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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Cyclin D1 as an Aid in the Diagnosis of Mantle Cell Lymphoma in Skin Biopsies: A Case Report

American Journal of Dermatopathology ◽

10.1097/00000372-200110000-00014 ◽

2001 ◽

Vol 23 (5) ◽

pp. 470-476 ◽

Cited By ~ 12

Author(s):

Brent R. Moody ◽

Nancy L. Bartlett ◽

David W. George ◽

Caroline R. Price ◽

Wayne A. Breer ◽

...

Keyword(s):

Case Report ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Mantle Cell ◽

Skin Biopsies

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Treatment options for mantle cell lymphoma

Expert Opinion on Pharmacotherapy ◽

10.1517/14656566.2015.1087507 ◽

2015 ◽

Vol 16 (16) ◽

pp. 2497-2507 ◽

Cited By ~ 8

Author(s):

Piotr Smolewski ◽

Magdalena Witkowska ◽

Tadeusz Robak

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Treatment Options ◽

Mantle Cell

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A Rare Prostate Pathology: Mantle Cell Lymphoma: A Case Report and Literature Review

Grand Journal of Urology ◽

10.5222/gju.2021.22931 ◽

2021 ◽

Author(s):

Selman Ünal ◽

Halil Uzundal ◽

Turker Soydaş ◽

Asım Özayar ◽

Arslan Ardıçoğlu ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Treatment Options ◽

Specific Antigen ◽

Rare Condition ◽

Additional Treatment ◽

Appropriate Treatment ◽

Histopathologic Diagnosis ◽

Mantle Cell ◽

Secondary Lymphoma

Primary or secondary lymphoma of the prostate is a rare condition. Mantle cell lymphoma (MCL) represent 4-9% of all lymphomas. Prostate involvement with MCL is very rare, with only 11 reported cases up to now. Here we present a case with lower urinary tract symptoms and prostate-specific antigen (PSA) elevation diagnosed with MCL of the prostate. Prostate biopsy was performed in a 70-year-old patient due to increased PSA. After the pathology result was reported as prostatic MCL, imaging studies and sampling of additional pathological specimens were performed for staging. An improvement was observed in the urinary system complaints of the patient who started chemotherapy regimen. While prostatectomy was performed in some of the prostatic MCL cases reported previously, in some, no additional treatment was required after chemotherapy. Our case is the only prostatic MCL case with elevated PSA levels, but did not receive the diagnosis of prostate cancer. Physicians should keep in mind that, prostatic MCL can present with nonspecific symptoms. Staging should be performed in patients whose histopathologic diagnosis is lymphoma of the prostate so as to determine appropriate treatment options.

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