Large-scale nuclear remodeling and transcriptional deregulation occur on both derivative chromosomes after Mantle Cell Lymphoma chromosomal translocation

ABSTRACTRecurrent chromosomal translocations are found in many blood and solid cancers. Balanced translocations, frequent in lymphoid malignancies, lead to the formation of two aberrant derivative (der) chromosomes. This event often leads to overexpression of an oncogene. In many cases, the expression of an oncogene is not enough to produce a malignant phenotype; however, most part of the studies focus on the events involving the chromosome where the oncogene is located, but rarely the other der chromosome where other oncogenic alterations may potentially arise. Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, is a perfect example of this. In 85% of the cases, it is characterized by the translocation t(11;14), which leads to the overexpression of cyclin D1 (CCND1) gene which results juxtaposed to the immunoglobulin heavy chain (IGH) gene on the der14 chromosome. This feature alone is not sufficient to induce oncogenesis. Here we focused on the der11 chromosome. We demonstrated that expression of 88 genes located in a 15mb region close to the translocation breakpoint on the der11 was deregulated both in the GRANTA-519 MCL cell line and in B-cells from MCL patients. We found that a large segment of der11containing deregulated genes was relocated from its normal position in the nuclear periphery towards the center of the nucleus in close proximity to the nucleolus where the abundant nucleolar protein nucleolin binds a subset of genes located close to the breakpoint and activates their expression. This finding allowed to identify new potential oncogenes involved in MCL and the mechanisms of their upregulation.

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A Multi-Target Drug Designing for BTK, MMP9, Proteasome And TAK1 for the clinical treatment of Mantle Cell Lymphoma

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210119112336 ◽

2021 ◽

Vol 21 ◽

Author(s):

Shahrukh Qureshi ◽

Ravina Khandelwal ◽

Maddala Madhavi ◽

Naveesha Khurana ◽

Neha Gupta ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Binding Capacity ◽

D1 Protein ◽

Chromosomal Translocation ◽

Non Hodgkin Lymphoma ◽

Target Drug ◽

Pubchem Compound ◽

Mantle Cell ◽

Protein Receptors

Background: Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma characterized by the mutation and overexpression of the cyclin D1 protein by the reciprocal chromosomal translocation t(11;14)(q13:q32). Aim: The Present study aims to identify a potential inhibition of MMP9, Proteasome, BTK, and TAK1 and also determine the most suitable and effective protein target for the MCL. Methodology: 9 known inhibitors for MMP9, 24 for proteasome, 15 for BTK and 14 for TAK1 were screened. SB-3CT (PubChem ID: 9883002), Oprozomib (PubChem ID: 25067547), Zanubrutinib (PubChem ID: 135565884) and TAK1 inhibitor (PubChem ID: 66760355) were recognized as drugs with high binding capacity with their respective protein receptors. 41, 72, 102 and 3 virtual screened compounds were obtained after the similarity search with compound (PubChem ID:102173753), PubChem compound SCHEMBL15569297 (PubChem ID:72374403), PubChem compound SCHEMBL17075298 (PubChem ID:136970120) and compound CID: 71814473 with best virtual screened compounds. Results : MMP9 inhibitors shows the commendable affinity and good interaction profile of compound holding PubChem ID:102173753 over the most effective established inhibitor SB3CT. The pharmacophore study of the best virtual screened compound reveals the high efficacy of compound based on various interactions. The better affinity of the virtual screened compound with the target MMP9 protein was deduced using toxicity and integration profile studies. Conclusion: On the basis of ADMET profile, compound (PubChem ID: 102173753) could be a potent drug for MCL treatment. Similar to the established SB-3CT, the compound was also found to be non-toxic with LD50 values for both the compounds lying in the same range.

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Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing

Blood ◽

10.1182/blood.2019002385 ◽

2020 ◽

Vol 136 (5) ◽

pp. 572-584 ◽

Cited By ~ 2

Author(s):

Prasath Pararajalingam ◽

Krysta M. Coyle ◽

Sarah E. Arthur ◽

Nicole Thomas ◽

Miguel Alcaide ◽

...

Keyword(s):

Protein Expression ◽

Mantle Cell Lymphoma ◽

Messenger Rna ◽

Large Scale ◽

Cell Lymphoma ◽

Genomic Analysis ◽

Feedback Mechanism ◽

Non Hodgkin Lymphoma ◽

Mantle Cell ◽

Using Data

Abstract Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.

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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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Pharmacokinetic profile and first preliminary clinical evaluation of bendamustine in Taiwanese patients with heavily pretreated indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma

Hematological Oncology ◽

10.1002/hon.2161 ◽

2014 ◽

Vol 33 (4) ◽

pp. 136-144 ◽

Cited By ~ 1

Author(s):

Liang-Tsai Hsiao ◽

Hwei-Fang Tien ◽

Ching-Yuan Kuo ◽

Jin-Hou Wu ◽

Hsin-An Hou ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Hodgkin Lymphoma ◽

Clinical Evaluation ◽

Cell Lymphoma ◽

Pharmacokinetic Profile ◽

Non Hodgkin Lymphoma ◽

Mantle Cell ◽

Heavily Pretreated

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Mantle Cell Lymphoma Mimicking Rectal Carcinoma

Case Reports in Hematology ◽

10.1155/2014/621017 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4

Author(s):

Engin Kelkitli ◽

Hilmi Atay ◽

Levent Yıldız ◽

Ahmet Bektaş ◽

Mehmet Turgut

Keyword(s):

Mantle Cell Lymphoma ◽

Hodgkin Lymphoma ◽

Rectal Carcinoma ◽

Cell Lymphoma ◽

Treatment Options ◽

Extranodal Involvement ◽

Non Hodgkin Lymphoma ◽

Rectal Involvement ◽

Mantle Cell ◽

Rectal Mass

Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma. After the (11;14) translocation was identified as its constant finding in 1992, MCL was recognized as a separate subgroup of non-Hodgkin lymphoma (NHL). In MCL, extranodal involvement may be observed in the bone marrow, the spleen, the liver, and the gastrointestinal system (GIS). Cases of MCL that present with a massive and solitary rectal mass are rare in the literature. In this case report, our aim was to present an MCL patient with a rarely observed solitary rectal involvement mimicking rectal carcinoma and to discuss treatment options for this patient.

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An open‐label phase 2 trial of entospletinib in indolent non‐Hodgkin lymphoma and mantle cell lymphoma

British Journal of Haematology ◽

10.1111/bjh.15552 ◽

2018 ◽

Vol 184 (2) ◽

pp. 215-222 ◽

Cited By ~ 15

Author(s):

David J. Andorsky ◽

Kathryn S. Kolibaba ◽

Sarit Assouline ◽

Andres Forero‐Torres ◽

Vicky Jones ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Hodgkin Lymphoma ◽

Cell Lymphoma ◽

Phase 2 ◽

Open Label ◽

Non Hodgkin Lymphoma ◽

Phase 2 Trial ◽

Mantle Cell ◽

Open Label Phase

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Front‐line management of indolent non‐Hodgkin lymphoma in Australia. Part 2: mantle cell lymphoma and marginal zone lymphoma

Internal Medicine Journal ◽

10.1111/imj.14268 ◽

2019 ◽

Vol 49 (9) ◽

pp. 1070-1080 ◽

Cited By ~ 4

Author(s):

Chan Y. Cheah ◽

Stephen Opat ◽

Judith Trotman ◽

Paula Marlton

Keyword(s):

Mantle Cell Lymphoma ◽

Hodgkin Lymphoma ◽

Marginal Zone ◽

Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Front Line ◽

Non Hodgkin Lymphoma ◽

Mantle Cell ◽

Line Management

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Mantle Cell Lymphoma Presenting as a Subcutaneous Mass of the Right Leg

Case Reports in Oncology ◽

10.1159/000507921 ◽

2020 ◽

Vol 13 (2) ◽

pp. 774-782

Author(s):

Drew A. Fajardo ◽

Joel France ◽

Bogna I. Targonska ◽

H. Bobby Kahlon ◽

Max J. Coppes

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

Non Hodgkin Lymphoma ◽

Mantle Cell ◽

History Of ◽

Subcutaneous Mass ◽

Systemic Symptoms ◽

The Right

Mantle cell lymphoma (MCL) is a relatively rare B-cell non-Hodgkin lymphoma, typically presenting with extensive lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal sites can also be involved. We discuss a 73-year-old man whose MCL presented with a 6-month history of a subdermal mass of the right upper thigh and no systemic symptoms.

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The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

Blood ◽

10.1182/blood-2010-11-314708 ◽

2011 ◽

Vol 117 (10) ◽

pp. 2807-2812 ◽

Cited By ~ 134

Author(s):

Jonathan W. Friedberg ◽

Julie M. Vose ◽

Jennifer L. Kelly ◽

Faith Young ◽

Steven H. Bernstein ◽

...

Keyword(s):

Adverse Events ◽

Mantle Cell Lymphoma ◽

Hodgkin Lymphoma ◽

Cell Lymphoma ◽

Objective Response ◽

Synergistic Activity ◽

Significant Activity ◽

Serious Adverse Events ◽

Non Hodgkin Lymphoma ◽

Mantle Cell

AbstractGiven the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m2 days 1 and 4; rituximab 375 mg/m2 day 1, and bortezomib 1.3 mg/m2 days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534.

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