Mantle Cell Lymphoma


Mantle cell lymphoma (MCL) is a B-cell lymphoma recognised in the Revised European-American Classification of Lymphoid Neoplasms (REAL) classification, 1994. MCL accounts for about 5% of adult non-Hodgkin lymphomas in the United States and Europe. It is characterised by a t(11;14)(q13;q32) translocation which juxtaposes the bcl-1 locus to the immunoglobulin (Ig) gene sequences and leads to deregulation of cyclin D1. Deletion of the ATM gene (11q22) is frequent in MCL.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Oligonucleotide Array Sequence Analysis
  • EZH2
  • Trisomy
  • B-Lymphocytes
  • Validation Studies as Topic
  • Mutation
  • Immunohistochemistry
  • MLL2
  • Chronic Lymphocytic Leukemia
  • ATM
  • Mantle-Cell Lymphoma
  • Chromosome 11
  • Oncogene Fusion Proteins
  • Chromosome Aberrations
  • Recurrence
  • Cyclin D1
  • Chromosome 14
  • Chromosome Deletion
  • Translocation
  • Protein Kinase Inhibitors
  • Ataxia Telangiectasia Mutated Proteins
  • Neprilysin
  • FISH
  • Base Sequence
  • Survival Rate
  • CCND2
  • VDJ Recombinases
  • Karyotyping
  • Triterpenes
  • Cell Proliferation
  • Gene Deletion
  • BIRC3
  • Gene Expression Profiling
  • Apoptosis
  • beta 2-Microglobulin
  • DNA-Binding Proteins
  • CCND1
  • Cancer DNA
  • Tumor Suppressor Proteins
  • Messenger RNA
  • p53 Protein
  • Cell Cycle Proteins
  • Cancer Gene Expression Regulation
  • Proportional Hazards Models
  • Sensitivity and Specificity
  • Immunoglobulin Heavy Chains
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (12)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

CCND1 11q13 BCL1, PRAD1, U21B31, D11S287E Translocation
-t(11;14)(q13;q32) in Mantle Cell Lymphoma
-CCND1 mutations in Mantle Cell Lymphoma
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 Translocation
-t(11;14)(q13;q32) in Mantle Cell Lymphoma
-IGH and Mantle-Cell Lymphoma
-ATM deletions in Mantle-Cell Lymphoma
TP53 17p13.1 P53, BCC7, LFS1, TRP53 GWS
-TP53 mutations in Mantle Cell Lymphoma
SOX11 2p25 MRD27 Overexpression
-SOX11 and Mantle-Cell Lymphoma
CCND2 12p13 MPPH3, KIAK0002 -CCND2 and Mantle-Cell Lymphoma
CCND3 6p21 -CCND3 and Mantle-Cell Lymphoma
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Mantle-Cell Lymphoma
EZH2 7q35-q36 WVS, ENX1, EZH1, KMT6, WVS2, ENX-1, EZH2b, KMT6A Overexpression
-EZH2 overexpression in Mantel Cell Lymphoma
KMT2D 12q13.12 ALR, KMS, MLL2, MLL4, AAD10, KABUK1, TNRC21, CAGL114 GWS
-MLL2 mutations in Mantle cell lymphoma
-BIRC3 mutation in Mantle Cell Lymphoma
-WHSC1 mutations in Mantle Cell Lymphoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

GWS - Genome/Exome Wide Study, large-scale/significant (selected):
Beà S et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(45):18250-5

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
t(11;14)(q13;q32) in Mantle Cell LymphomaTranslocationCCND1 (11q13)IGH (14q32.33)

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Latest Publications

Ji H, Tang Y, He Y, et al.
[Correlation of immunoglobulin variable heavy chain gene mutation status with prognosis in patients with mantle cell lymphoma].
Zhonghua Bing Li Xue Za Zhi. 2015; 44(2):90-4 [PubMed] Related Publications
OBJECTIVE: To study the relationship between immunoglobulin variable heavy chain (IgVH) gene mutation status and clinical features, pathologic findings and biologic behavior of mantle cell lymphoma (MCL).
METHODS: IgVH gene was amplified in 60 cases of MCL with FR1-JH and FR2-JH primers in BIOMED-2. The sequence was determined by cloning. The IgVH somatic mutational status was analyzed using NCBI's Ig-Blast tool. The relationship between IgVH gene mutation status and clinicopathologic features was also analyzed.
RESULTS: Forty percent (24 cases, 28 functional Ig genes) of the MCL cases displayed somatically mutated VH genes (defined as > 2% mutated), whereas 60.0% (36 cases, 40 functional Ig genes) showed unmutated VH genes. The most widely used genes were VH3-21 (27.9%) and VH4-34 (19.1%). The former were mainly used by unmutated cases, while the later mainly by mutated cases.Intraclonal heterogeneity was noted in 19 cases. There was no correlation of VH mutation status and specific VH gene with survival (P > 0.05).
CONCLUSIONS: MCL comprises at least two subsets that do not correlate with morphology: one with unmutated VH genes and one with mutated VH genes. The biased use of VH3-21 and VH4-34 is noted. The nonrandom usage of IgVH segments suggests specific antigens may play a role in the pathogenesis and progression of MCL subsets. There is no correlation of IgVH mutation status and specific VH gene with survival.

Husby S, Ralfkiaer U, Garde C, et al.
miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator.
Blood. 2015; 125(17):2669-77 [PubMed] Related Publications
Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.

Ondrejka SL, Hsi ED
Pathology of B-cell lymphomas: diagnosis and biomarker discovery.
Cancer Treat Res. 2015; 165:27-50 [PubMed] Related Publications
The diagnosis of B-cell non-Hodgkin lymphomas has changed significantly over the past few decades as new immunophenotypic markers, molecular subtype classification schemes, and novel biomarkers have emerged. Meanwhile, there has been an increasing emphasis on individualizing treatment approaches in accordance with a biologic heterogeneity that has been uncovered within many of the individual B-cell lymphoma entities. The application of high-throughput genomic sequencing to B-cell lymphomas has yielded large amounts of valuable information. The data encompass discoveries essential to an understanding of pathogenesis, clonal or tumoral evolution, and identification of biomarkers that may be useful for prognostic or therapeutic considerations. The following review discusses several of the more common, primarily tissuebased B-cell lymphomas, with a focus on pathologic classification and certain phenotypic characteristics or genetic lesions that apply to refinement of diagnosis and therapy.

Huang YQ, Huang XL, Ma XD
[Effect of silencing NOTCH1 gene by shRNA interference on AKT/mTOR pathway in mantle cell lymphoma].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014; 22(6):1616-20 [PubMed] Related Publications
The study was purposed to investigate the effect of silencing NOTCH1 gene by shRNA interference on the proliferation, apoptosis and the expression of AKT signaling pathway-related proteins in mantle cell lymphoma Jeko-1 cell line. The hairpin-like oligonucleotide sequences targeting NOTCH1 gene were designed and transfected into Jeko-1 cells by lipofectamine (TM) 2 000. NOTCH1 mRNA and protein were detected respectively by RT-PCR and Western blot. Cell growth was determined by MTT. Cell apoptosis was analyzed by flow cytometry. The expressions of BCL-2, BAX, procaspase-3, procaspase-9, Akt, p-Akt, p-mTOR, p-P70S6K were detected by Western blot. The results showed that NOTCH1 mRNA expression was markedly suppressed by the shRNA targeting NOTCH1. NOTCH1 shRNA suppressed the proliferation of Jeko-1 cells and induced apoptosis of these cells. The cell apoptotic rate was (34.5 ± 3.4)%, (2.4 ± 1.3) %, (1.7 ± 0.6) % in NOTCH1 shRNA, Neg-shRNA and blank groups, respectively, and the difference between them was statistically significant (P < 0.01). NOTCH1 shRNA down-regulated the expression of BCL-2, procaspase-3, procaspase 9, p-Akt, p-mTOR and p-70S6K, up-regulated the expression of BAX, but no change protein expression of Akt was observed. It is concluded that the silencing NOTCH1 gene expression by shRNA interference may inhibit Jeko-1 proliferation, induce the cell apoptosis, and the mechanisms may be associated with the inhibition of Akt/mTOR signaling pathway by dephosphorylation.

Campo E, Rule S
Mantle cell lymphoma: evolving management strategies.
Blood. 2015; 125(1):48-55 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin's lymphoma that generally affects older individuals and continues to have one of the worst outcomes of all the lymphomas. Over the last decade, there has been a widespread adoption of cytarabine-based therapy in younger patients, and the incorporation of rituximab into chemotherapeutic regimens has become an evidence-based standard of care. However MCL remains a largely incurable disease, and following relapse, it can be a challenge to manage. Although it is possible to define prognosis reliably, there are, as yet, no clear diagnostic or response-adjusted parameters that can help to guide therapeutic decisions. However, there are a number of highly active targeted therapies that are moving into the clinic that are set to transform the therapeutic paradigm for this disease in the very near future. This review will explore the molecular pathogenesis of MCL and the current and evolving therapeutic strategies for this disease.

Kiebala M, Skalska J, Casulo C, et al.
Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach.
Exp Hematol. 2015; 43(2):89-99 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined nontoxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin system, with nontoxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. Auranofin interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle-cell lymphoma cells. Additionally, there was less toxicity toward normal B cells. Low AUR concentrations inhibited thioredoxin reductase (TrxR) activity, an effect significantly increased by BSO cotreatment. Overexpression of TrxR partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited nuclear factor κB (NF-κB) signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells overexpressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death. Together, these findings suggest that AUR+BSO synergistically induces malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies.

Baumann U, Fernández-Sáiz V, Rudelius M, et al.
Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis.
Nat Med. 2014; 20(12):1401-9 [PubMed] Related Publications
We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eμ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.

Bernard S, Danglade D, Gardano L, et al.
Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma.
Int J Cancer. 2015; 136(12):2761-74 [PubMed] Related Publications
Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B-cell receptor (BCR)-mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR-associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL-1β, IL-6, IL-8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL-1β, IL-6, IL-8, CCL5, IL-10, TNFα and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR-induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR-induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short- and long-term co-culture. We demonstrated that BCR-induced survival relies on autocrine secretion of IL-1β, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis.

Yim RL, Wong KY, Kwong YL, et al.
Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas.
Oncotarget. 2014; 5(20):9770-82 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma (NHL). In cancers, tumor suppressive microRNAs may be silenced by DNA hypermethylation. By microRNA profiling of representative EBV-negative MCL cell lines before and after demethylation treatment, miR-155-3p was found significantly restored. Methylation-specific PCR, verified by pyrosequencing, showed complete methylation of miR-155-3p in one MCL cell line (REC-1). 5-aza-2'-deoxycytidine treatment of REC-1 led to demethylation and re-expression of miR-155-3p. Over-expression of miR-155-3p led to increased sub-G1 apoptotic cells and reduced cellular viability, demonstrating its tumor suppressive properties. By luciferase assay, lymphotoxin-beta (LT-β) was validated as a miR-155-3p target. In 31 primary MCL, miR-155-3p was found hypermethylated in 6(19%) cases. To test if methylation of miR-155-3p was MCL-specific, miR-155-3p methylation was tested in an additional 191 B-cell, T-cell and NK-cell NHLs, yielding miR-155-3p methylation in 66(34.6%) including 36(27%) non-MCL B-cell, 24(53%) T-cell and 6(46%) of NK-cell lymphoma. Moreover, in 72 primary NHL samples with RNA, miR-155-3p methylation correlated with miR-155-3p downregulation (p=0.024), and LT-β upregulation (p=0.043). Collectively, miR-155-3p is a potential tumor suppressive microRNA hypermethylated in MCL and other NHL subtypes. As miR-155-3p targets LT-β, which is an upstream activator of the non-canonical NF-kB signaling, miR-155-3p methylation is potentially important in lymphomagenesis.

Tang T, Martin P
Mantle cell lymphoma: taking therapeutic advantage of new insights into the biology.
Curr Hematol Malig Rep. 2014; 9(3):254-61 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is an uncommon, incurable B-cell non-Hodgkin's lymphoma that afflicts the elderly. There is no standard course of treatment, with options varying from observation in asymptomatic patients to aggressive induction/consolidation regimens in younger patients with rapidly progressive disease. Emerging data regarding the role of the ubiquitin-proteasome system, B-cell receptor and mTOR signaling pathways, cell cycle regulation, and epigenetic and immune-modulation in the pathogenesis of MCL have resulted in the development of novel therapies, with a shift away from conventional cytotoxic chemotherapy to relatively less toxic, more targeted treatment. The challenge now is to determine the optimal sequence and combination of the various available and emerging therapies for use in patients with MCL.

Klanova M, Lorkova L, Vit O, et al.
Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents.
Mol Cancer. 2014; 13:159 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive.
METHODS: Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies.
RESULTS: Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts.
CONCLUSIONS: Acquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.

van der Velden VH, Hoogeveen PG, de Ridder D, et al.
B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma.
Blood. 2014; 124(3):412-9 [PubMed] Related Publications
B-cell prolymphocytic leukemia (B-PLL) is a rare mature B-cell malignancy that may be hard to distinguish from mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). B-PLL cases with a t(11;14) were redefined as MCL in the World Health Organization 2008 classification. We evaluated 13 B-PLL patients [7 being t(11;14)-positive (B-PLL+) and 6 negative (B-PLL-)] and compared them with MCL and CLL patients. EuroFlow-based immunophenotyping showed significant overlap between B-PLL+ and B-PLL-, as well as between B-PLL and MCL, whereas CLL clustered separately. Immunogenotyping showed specific IGHV gene usage partly resembling MCL. Gene expression profiling showed no separation between B-PLL+ and B-PLL- but identified 3 subgroups. One B-PLL subgroup clustered close to CLL and another subgroup clustered with leukemic MCL; both were associated with prolonged survival. A third subgroup clustered close to nodal MCL and was associated with short survival. Gene expression profiles of both B-PLL+ and B-PLL- showed best resemblance with normal immunoglobulin M-only B-cells. Our data confirm that B-PLL+ is highly comparable to MCL, indicate that B-PLL- also may be considered as a specific subgroup of MCL, and suggest that B-PLL is part of a spectrum, ranging from CLL-like B-PLL, to leukemic MCL-like B-PLL, to nodal MCL-like B-PLL.

Simonsen AT, Sørensen CD, Ebbesen LH, et al.
SOX11 as a minimal residual disease marker for Mantle cell lymphoma.
Leuk Res. 2014; 38(8):918-24 [PubMed] Related Publications
Recent studies have identified SOX11 as a novel diagnostic marker for mantle cell lymphoma (MCL). We quantified SOX11 by a truly mRNA specific qPCR assay in longitudinal peripheral blood samples from 20 patients and evidenced a close relationship of SOX11 expression and clinical status of the patients. In eight patient courses we validated the expression of SOX11 using t(11;14) and demonstrated positive correlation of SOX11 and t(11;14) levels. To the best of our knowledge this is the first report stating that quantification of SOX11 can be used as an minimal residual disease marker equal to the key translocation t(11;14) in MCL.

Klanova M, Soukup T, Jaksa R, et al.
Mouse models of mantle cell lymphoma, complex changes in gene expression and phenotype of engrafted MCL cells: implications for preclinical research.
Lab Invest. 2014; 94(7):806-17 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) associated with poor prognosis. Animal models of MCL are scarce. We established and characterized various in vivo models of metastatic human MCL by tail vein injection of either primary cells isolated from patients with MCL or established MCL cell lines (Jeko-1, Mino, Rec-1, Hbl-2, and Granta-519) into immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. MCL infiltration was assessed with immunohistochemistry (tissues) and flow cytometry (peripheral blood). Engraftment of primary MCL cells was observed in 7 out of 12 patient samples. The pattern of engraftment of primary MCL cells varied from isolated involvement of the spleen to multiorgan infiltration. On the other hand, tumor engraftment was achieved in all five MCL cell lines used and lymphoma involvement of murine bone marrow, spleen, liver, and brain was observed. Overall survival of xenografted mice ranged from 22 ± 1 to 54 ± 3 days depending on the cell line used. Subsequently, we compared the gene expression profile (GEP) and phenotype of the engrafted MCL cells compared with the original in vitro growing cell lines (controls). We demonstrated that engrafted MCL cells displayed complex changes of GEP, protein expression, and sensitivity to cytotoxic agents when compared with controls. We further demonstrated that our MCL mouse models could be used to test the therapeutic activity of systemic chemotherapy, monoclonal antibodies, or angiogenesis inhibitors. The characterization of MCL murine models is likely to aid in improving our knowledge in the disease biology and to assist scientists in the preclinical and clinical development of novel agents in relapsed/refractory MCL patients.

Chapman-Fredricks J, Sandoval-Sus J, Vega F, Lossos IS
Progressive leukemic non-nodal mantle cell lymphoma associated with deletions of TP53, ATM, and/or 13q14.
Ann Diagn Pathol. 2014; 18(4):214-9 [PubMed] Related Publications
Leukemic, non-nodal mantle cell lymphoma (MCL) is a relatively indolent disease characterized by asymptomatic leukemic presentation, non-nodal disease distribution, and slow disease progression, particularly in comparison to that of classic nodal MCL. We studied 3 cases of leukemic, non-nodal MCL in which TP53, ATM, and/or 13q14 deletions were identified. All three patients had disease progression leading to treatment requirements in two of the patients at 5 and 18 months after initial diagnosis. The third patient also clinically progressed 25 months after initial diagnosis but was lost to follow up despite recommendation for initiation of therapy. We present these cases as potential evidence that while leukemic non-nodal MCL is typically an indolent disease compared to classically defined mantle cell lymphoma, cytogenetic heterogeneity exists and cases with TP53, ATM, and/or 13q14 deletions may have a relatively aggressive clinical course.

Yoshimura M, Ishizawa J, Ruvolo V, et al.
Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma.
Cancer Sci. 2014; 105(7):795-801 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The nuclear transporter exportin-1 (XPO1) is highly expressed in mantle cell lymphoma (MCL) cells, and is believed to be associated with the pathogenesis of this disease. XPO1-selective inhibitors of nuclear export (SINE) compounds have been shown to induce apoptosis in MCL cells. Given that p53 is a cargo protein of XPO1, we sought to determine the significance of p53 activation through XPO1 inhibition in SINE-induced apoptosis of MCL cells. We investigated the prognostic impact of XPO1 expression in MCL cells using Oncomine analysis. The significance of p53 mutational/functional status on sensitivity to XPO1 inhibition in cell models and primary MCL samples, and the functional role of p53-mediated apoptosis signaling, were also examined. Increased XPO1 expression was associated with poor prognosis in MCL patients. The XPO1 inhibitor KPT-185 induced apoptosis in MCL cells through p53-dependent and -independent mechanisms, and p53 status was a critical determinant of its apoptosis induction. The KPT-185-induced, p53-mediated apoptosis in the MCL cells occurred in a transcription-dependent manner. Exportin-1 appears to influence patient survival in MCL, and the SINE XPO1 antagonist KPT-185 effectively activates p53-mediated transcription and apoptosis, which would provide a novel strategy for the therapy of MCL.

Roisman A, Slavutsky I
[Expression of SOX11 transcription factor. Its implication in mantle cell lymphoma].
Medicina (B Aires). 2014; 74(2):140-6 [PubMed] Related Publications
SOX11, belonging to the family of genes SOXC, is a transcript factor involved in the embryonic neurogenesis and tissue remodeling, also participating in the control of cell proliferation. Its role in lymphomagenesis still remains unknown. Recent studies have shown aberrant SOX11 nuclear protein expression as well as mRNA levels in patients with mantle cell lymphoma (MCL). Although the majority of these lymphomas have an aggressive clinical course, there is a subgroup of patients with an indolent clinical evolution, suggesting a greater heterogeneity of this disease. Currently, there are contradictions regarding the association of SOX11 gene expression and outcome in MCL, while some authors have related the lack of SOX11 expression with good prognosis, others find it associated with an adverse clinical course. This difference in the gene expression could be associated to epigenetic mechanisms such as modifications at the histone level and DNA methylation that would allow the aberrant expression of this gene in some lymphoid neoplasias, including LCM. More knowledge of gene SOX11 in LCM will lead to a greater understanding of those mechanisms involved in the pathogenesis and progression of this lymphoma, also the involvement of SOX11 in these processes.

Juskevicius D, Ruiz C, Dirnhofer S, Tzankov A
Clinical, morphologic, phenotypic, and genetic evidence of cyclin D1-positive diffuse large B-cell lymphomas with CYCLIN D1 gene rearrangements.
Am J Surg Pathol. 2014; 38(5):719-27 [PubMed] Related Publications
Overexpression of cyclin D1 in diffuse large B-cell lymphomas (DLBCLs) is observable in about 5% of cases and is linked to gains of additional CYCLIN D1 gene copies or deregulation at the mRNA level. All cyclin D1-positive DLBCL cases reported so far lack the canonical t(11;14)(q13;q32) translocation that is a genetic hallmark and the primary cause of cyclin D1 overexpression in mantle cell lymphoma (MCL). Using standard histologic and genetic techniques, complemented with genome-wide aberration analysis by array comparative genomic hybridization, we characterized 2 exceptional cases of blastoid B-cell lymphomas with cyclin D1 overexpression, both bearing genetic rearrangements in the CYCLIN D1 gene locus. One of them had a t(11;14)(q13;q32) translocation and featured morphology, immunophenotype, and genetic copy number aberrations typical of DLBCL. The second case had a complex t(4;11;14) translocation, but the other features were intermediate between DLBCL and MCL and did not allow unambiguous classification in any of the current diagnostic lymphoma categories. On the basis of these findings, we conclude that detection of t(11;14) should not preclude a diagnosis of cyclin D1-positive DLBCL when all other parameters are in agreement with such a diagnosis. Moreover, a yet unacknowledged diagnostic "gray zone" may exist between DLBCL and MCL.

Mourtada-Maarabouni M, Williams GT
Role of GAS5 noncoding RNA in mediating the effects of rapamycin and its analogues on mantle cell lymphoma cells.
Clin Lymphoma Myeloma Leuk. 2014; 14(6):468-73 [PubMed] Related Publications
BACKGROUND: Inhibition of the mammalian target of rapamycin (mTOR) pathway is a promising strategy for the treatment of mantle cell lymphoma (MCL). ncRNA growth arrest-specific 5 (GAS5), a 5' terminal oligopyrimidine (5'TOP) RNA regulated by the mTOR pathway, is necessary and sufficient for normal growth arrest in leukemic and untransformed human lymphocytes.
METHODS: We downregulated endogenous GAS5 in mantle cell lymphoma cell lines using RNA interference before treatment with several rapalogues. The effect of GAS5 downregulation was monitored by 3 independent analyses of cell viability, DNA synthesis, and colony-forming ability.
RESULTS: Downregulation of GAS5 substantially reduced the effects of each rapalogue on cell viability, DNA synthesis, and colony-forming ability.
CONCLUSION: Stimulation of expression of candidate tumor suppressor GAS5 is responsible for much of the cytotoxic and cytostatic effects of rapalogues in MCL, suggesting that improved targeting of this pathway may allow improvements in the therapy of this intractable lymphoma.

de Oliveira FM, Rodrigues-Alves AP, Lucena-Araújo AR, et al.
Mantle cell lymphoma harboring Burkitt's-like translocations presents differential expression of aurora kinase genes compared with others 8q abnormalities.
Med Oncol. 2014; 31(5):931 [PubMed] Related Publications
We compared the levels of AURKA and AURKB in 24 (mantle cell lymphoma) MCL patients harboring 8q abnormalities and its relationship with MYCC gene status. Two distinct subgroups were observed, in terms of MYCC expression. Except for the patients with Burkitt's-like translocation, none of the patients harboring 8q abnormalities, including balanced translocations or duplications of MYCC band, identified both by G-banding and SKY, showed differential expression levels of MYCC. These previous findings also reflected in the differential expression of AURKA and AURKB genes. We found that AURKA and AURKB mRNA were expressed at significantly higher levels in MCL patients harboring Burkitt's-like translocation, when compared to patients with 8q rearrangements. The high expression of aurora kinase genes is reported to be associated with some parameters of clinical oncologic aggressiveness, such as high histological grade, invasion and increased rates of metastasis in several types of cancers. It is possible that in MCL patients expressing abnormal levels of MYCC together with a high expression of AURKA might offer some resistant to the conventional therapy purposes. Thus, aurora kinase inhibitors may also be considered for this specific subgroup on MCL, whose aggressive clinical course resembles high-grade lymphoma.

Zhang J, Jima D, Moffitt AB, et al.
The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells.
Blood. 2014; 123(19):2988-96 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.

Kuo PY, Leshchenko VV, Fazzari MJ, et al.
High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma.
Oncogene. 2015; 34(10):1231-40 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.

Beà S
Cyclin D1 transcriptional activation in MCL.
Blood. 2014; 123(13):1979-80 [PubMed] Related Publications
In this issue of Blood, Allinne et al propose the nucleolin-dependent activation of the translocated CCND1 allele in mantle cell lymphoma (MCL) because of its relocalization to a transcriptionally favorable area in the perinucleolar region.

Ok CY, Xu-Monette ZY, Tzankov A, et al.
Prevalence and clinical implications of cyclin D1 expression in diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program.
Cancer. 2014; 120(12):1818-29 [PubMed] Related Publications
BACKGROUND: Cyclin D1 expression has been reported in a subset of patients with diffuse large B-cell leukemia (DLBCL), but studies have been few and generally small, and they have demonstrated no obvious clinical implications attributable to cyclin D1 expression.
METHODS: The authors reviewed 1435 patients who were diagnosed with DLBCL as part of the International DLBCL rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) Consortium Program and performed clinical, immunohistochemical, and genetic analyses with a focus on cyclin D1. All patients who were cyclin D1-positive according to immunohistochemistry were also assessed for rearrangements of the cyclin D1 gene (CCND1) using fluorescence in situ hybridization. Gene expression profiling was performed to compare patients who had DLBCL with and without cyclin D1 expression.
RESULTS: In total, 30 patients (2.1%) who had DLBCL that expressed cyclin D1 and lacked CCND1 gene rearrangements were identified. Patients with cyclin D1-positive DLBCL had a median age of 57 years (range, 16.0-82.6 years). There were 23 males and 7 females. Twelve patients (40%) had bulky disease. None of them expressed CD5. Two patients expressed cyclin D2. Gene expression profiling indicated that 17 tumors were of the germinal center type, and 13 were of the activated B-cell type. Genetic aberrations of B-cell leukemia/lymphoma 2 (BCL2), BCL6, v-myc avian myelocytomatosis viral oncogene homolog (MYC), mouse double minute 2 oncogene E3 ubiquitin protein ligase (MDM2), MDM4, and tumor protein 53 (TP53) were rare or absent. Gene expression profiling did not reveal any striking differences with respect to cyclin D1 in DLBCL.
CONCLUSIONS: Compared with patients who had cyclin D1-negative DLBCL, men were more commonly affected with cyclin D1-positive DLBCL, and they were significantly younger. There were no other significant differences in clinical presentation, pathologic features, overall survival, or progression-free survival between these two subgroups of patients with DLBCL.

Sørensen CD, Jørgensen JM, Nederby L, et al.
Common consensus LNA probe for quantitative PCR assays in cancer: vehicles for minimal residual disease detection in t(11;14) and t(14;18) positive malignant lymphomas.
J Immunol Methods. 2014; 406:131-6 [PubMed] Related Publications
The use of locked nucleic acid (LNA) probes and primers potentially improves sensitivity and specificity of quantitative PCR (qPCR) assays. One area of application is that of minimal residual cancer where PCR techniques have proved to be highly relevant tools in patient follow-up. We present here sensitive and specific consensus qPCR assays for quantification of the malignant lymphoma translocations, t(11;14) and t(14;18), by taking advantage of the thermodynamic properties of LNA. The assays were applied to genomic DNA from patients diagnosed with mantle cell lymphoma (MCL) and follicular lymphoma (FL), respectively. Two consensus forward primers targeting the BCL1 and BCL2 genes were designed together with a common consensus reverse primer and hydrolysis probe, the latter consisting exclusively of LNA, both targeting the J segments of the immunoglobulin heavy chain (IgH) gene. The quantitative range of both assays was 1×10(0) to 5×10(-5), and the sensitivity was 10(-5), without the need for patient-specific primers. Peripheral blood (PB) and bone marrow (BM) samples from 36 patients diagnosed with MCL and nine patients diagnosed with FL were analysed using this novel qPCR approach. The level of minimal residual disease (MRD) using t(11;14) and t(14;18) as genetic targets reflected the clinical status of the patients: low levels of MRD at clinical remission, and increasing levels at disease progression. The present assays could prove as useful tools in lymphoma therapy.

Ogura M, Ando K, Suzuki T, et al.
A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma.
Br J Haematol. 2014; 165(6):768-76 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.

Dengler MA, Weilbacher A, Gutekunst M, et al.
Discrepant NOXA (PMAIP1) transcript and NOXA protein levels: a potential Achilles' heel in mantle cell lymphoma.
Cell Death Dis. 2014; 5:e1013 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with transient response to conventional chemotherapy. We here investigated the role of the Bcl-2 homology domain 3-only protein NOXA for life-death decision in MCL. Surprisingly, NOXA (PMAIP1) mRNA and NOXA protein levels were extremely discrepant in MCL cells: NOXA mRNA was found to be highly expressed whereas NOXA protein levels were low. Chronic active B-cell receptor signaling and to a minor degree cyclin D1 overexpression contributed to high NOXA mRNA expression levels in MCL cells. The phoshatidyl-inositol-3 kinase/AKT/mammalian target of rapamycin pathway was identified as the major downstream signaling pathway involved in the maintenance of NOXA gene expression. Interestingly, MCL cells adapt to this constitutive pro-apoptotic signal by extensive ubiquitination and rapid proteasomal degradation of NOXA protein (T½∼15-30 min). In addition to the proteasome inhibitor Bortezomib, we identified the neddylation inhibitor MLN4924 and the fatty acid synthase inhibitor Orlistat as potent inducers of NOXA protein expression leading to apoptosis in MCL. All inhibitors targeted NOXA protein turnover. In contrast to Bortezomib, MLN4924 and Orlistat interfered with the ubiquitination process of NOXA protein thereby offering new strategies to kill Bortezomib-resistant MCL cells. Our data, therefore, highlight a critical role of NOXA in the balance between life and death in MCL. The discrepancy between NOXA transcript and protein levels is essential for sensitivity of MCL to ubiquitin-proteasome system inhibitors and could therefore provide a druggable Achilles' heel of MCL cells.

Allinne J, Pichugin A, Iarovaia O, et al.
Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of key genes in mantle cell lymphoma.
Blood. 2014; 123(13):2044-53 [PubMed] Related Publications
In mantle cell lymphoma (MCL), one allele of the cyclin D1 (Ccnd1) gene is translocated from its normal localization on chromosome 11 to chromosome 14. This is considered as the crucial event in the transformation process of a normal naive B-cell; however, the actual molecular mechanism leading to Ccnd1 activation remains to be deciphered. Using a combination of three-dimensional and immuno-fluorescence in situ hybridization experiments, the radial position of the 2 Ccnd1 alleles was investigated in MCL-derived cell lines and malignant cells from affected patients. The translocated Ccnd1 allele was observed significantly more distant from the nuclear membrane than its nontranslocated counterpart, with a very high proportion of IgH-Ccnd1 chromosomal segments localized next to a nucleolus. These perinucleolar areas were found to contain active RNA polymerase II (PolII) clusters. Nucleoli are rich in nucleolin, a potent transcription factor that we found to bind sites within the Ccnd1 gene specifically in MCL cells and to activate Ccnd1 transcription. We propose that the Ccnd1 transcriptional activation in MCL cells relates to the repositioning of the rearranged IgH-Ccnd1-carrying chromosomal segment in a nuclear territory with abundant nucleolin and active PolII molecules. Similar transforming events could occur in Burkitt and other B-cell lymphomas.

Katz SG, Labelle JL, Meng H, et al.
Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells.
Blood. 2014; 123(6):884-93 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exerts its pro-death function via its α-helical BH3 death domain that has the dual capacity to inhibit antiapoptotic proteins such as BCL-2 and MCL-1 and directly trigger proapoptotic proteins such as the mitochondrial executioner protein BAX. To evaluate a functional role for Bim deletion in the pathogenesis of MCL, we generated cyclin D1-transgenic mice harboring Bim-deficient B cells. In response to immunization, Eμ(CycD1)CD19(CRE)Bim(fl/fl) mice manifested selective expansion of their splenic mantle zone compartment. Three distinct immune stimulation regimens induced lymphomas with histopathologic and molecular features of human MCL in a subset of mice. Thus, deletion of Bim in B cells, in the context of cyclin D1 overexpression, disrupts a critical control point in lymphoid maturation and predisposes to the development of MCL. This genetic proof of concept for MCL pathogenesis suggests an opportunity to reactivate the death pathway by pharmacologic mimicry of proapoptotic BIM.

Ladetto M, Brüggemann M, Monitillo L, et al.
Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders.
Leukemia. 2014; 28(6):1299-307 [PubMed] Related Publications
In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next-generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 × E-05. A good correlation of MRD results was observed (R=0.791, P<0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele-specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment.

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