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

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

10.1101/2019.12.30.882407 ◽

2019 ◽

Author(s):

Fatimata Bintou Sall ◽

Andrei Pichugin ◽

Olga Iarovaia ◽

Ana Barat ◽

Tatyana Tsfasman ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Large Scale ◽

Cell Lymphoma ◽

Nuclear Periphery ◽

Chromosomal Translocation ◽

Non Hodgkin Lymphoma ◽

Close Proximity ◽

Mantle Cell ◽

Balanced Translocations ◽

Nuclear Remodeling

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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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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Using the primary site as a prognostic tool for nodal mantle cell lymphoma: a SEER-based study

Journal of Comparative Effectiveness Research ◽

10.2217/cer-2020-0083 ◽

2020 ◽

Vol 9 (12) ◽

pp. 861-876

Author(s):

Mohamed Gomaa Kamel ◽

Amr Ehab El-Qushayri ◽

Ahmed Kamal Sayed ◽

Nguyen Tien Huy

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Primary Site ◽

Cancer Specific Survival ◽

Mantle Cell ◽

Multiple Regions ◽

Using Data

Background: Nodal mantle cell lymphoma (NMCL) has a worse survival than extra-nodal mantle cell lymphoma. Materials & methods: A cohort study was conducted to evaluate the primary site role as a mortality predictor using data from 1983 to 2011 from the Surveillance, Epidemiology, and End Results (SEER) database. Results: Most patients had NMCL in multiple regions (71.9%). There was a significantly increased incidence of NMCL cases over years with 83.2% of them occurred between 1998 and 2011. The mean survival was 52.9 months with overall survival/cancer-specific survival rate of 29.2/42.9%, respectively. Lymph nodes of intrathoracic and multiple regions had a worse overall survival while the head, face and neck, intra-abdominal, pelvic, inguinal region and leg as well as multiple regions had worse cancer-specific survival. Conclusion: NMCL primary site can serve as a prognostic factor. We encourage adding it to MCL International Prognostic Index.

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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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Truncations in CCND1 mRNA 3′ UTR Alters microRNA Regulation in Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.3184.3184 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3184-3184

Author(s):

Robert W. Chen ◽

Lynne Bemis ◽

Carol Amato ◽

Birks Diane ◽

Myint Han ◽

...

Keyword(s):

Cell Cycle ◽

Protein Expression ◽

Mantle Cell Lymphoma ◽

Cell Line ◽

Cell Lymphoma ◽

Regulation Of Gene Expression ◽

Proliferative Potential ◽

Transcriptional Level ◽

Cell Cycle Regulator ◽

Mantle Cell

Abstract Mantle Cell Lymphoma (MCL) represents only 5–10% of all non-Hodgkins lymphomas, making it an uncommon but difficult form of lymphoma to treat. It has a poor prognosis among the B cell lymphomas with median survival of three years. The genetic hallmark of MCL is the t(11,14) translocation causing amplification of cyclin D1 (CCND1), a known cell cycle regulator which is overexpressed in many other cancers. MicroRNAs (miRNA) are a new class of abundant small RNAs that play important regulatory roles at the post transcriptional level. They act by binding to the 3′ untranslated region (UTR) of mRNAs and block either their translation or initiate their degradation. Recent reports have shown truncations in the CCND1 3′ UTR occur in MCL and indicate a worse prognosis. We hypothesized that truncations in 3′ UTR of CCND1 alter it’s regulation by microRNAs. Based on bioinformatics, we identified microRNA 16 with putative docking sites in the 3′UTR of CCND1. Mir-16 has been implicated as a cell cycle regulator. We identified 2 cell lines (Jeko-1 and Z138) with truncations in CCND1 3′ UTR and demonstrated increased CCND1 mRNA expression by qRT-PCR, increased protein expression by western blot, and higher proliferative potential by cell cycle. We prepared a reporter construct by ligating the full length 3′ UTR of CCND1 to GFP. We then co-transfected this construct with mimics of mir-16 into a cancer cell line and demonstrated downregulation of CCND1 protein expression by flow cytometry. In the MCL cell line Granta-519 with non-truncated CCND1, transfection with mimics of mir-16 deminstrated decreased expression of CCND1 mRNA. These studies suggest that the overexpression of CCDN1 In MCL may result from altered regulation of gene expression from loss of a miRNA regulatory site and may give new clues into the patho-biology of this disease and insights into possible new therapies.

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