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Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics

Key Points

  • Mantle cell lymphoma (MCL) is a lymphoid neoplasm characterized by an abnormal proliferation of mature B lymphocytes, which probably derive from naive B cells expressing CD5. This tumour is considered one of the most aggressive lymphoid neoplasms, with poor responses to conventional chemotherapy and relatively short survival. A subset of patients with a more indolent clinical course has been recognized.

  • The genetic hallmark of this neoplasm is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which has an important pathogenetic role, probably deregulating cell cycle control by overcoming the suppressor effect of retinoblastoma 1 (RB1) and the cell cycle inhibitor p27.

  • In addition to this translocation, MCL tumour cells carry a high number of secondary chromosomal and molecular alterations targeting proteins that regulate the cell cycle and senescence (BMI1, INK4a, ARF, CDK4 and RB1) and interfere with the cellular response to DNA damage (ATM, CHK2 and p53).

  • The clinical evolution of patients with MCL is very variable. At present, the quantification of the proliferative activity of the tumour is the best survival predictor, but a more precise evaluation of patient prognosis, through the study of specific chromosomal alterations, may help to design more tailored therapies.

  • New therapeutic strategies that target cell pathways deregulated in these tumours are opening new possibilities for the treatment of patients with MCL. Specifically, compounds that interfere with cell proliferation mechanisms, which actively promote apoptosis or inhibit the survival signals of tumour cells, have provided promising results in preclinical models and preliminary clinical trials. A thorough understanding of the mechanisms of action of these drugs may help to design more rational strategies.

Abstract

Mantle cell lymphoma (MCL) is a well-defined lymphoid malignancy characterized by a rapid clinical evolution and poor response to current therapeutic protocols. The genetic and molecular mechanisms involved in its pathogenesis combine the dysregulation of cell proliferation and survival pathways with a high level of chromosome instability that seems related to the disruption of the DNA damage response pathway. Understanding these mechanisms and how they affect tumour behaviour is providing the rationale for the identification of reliable predictors of clinical evolution and the design of innovative therapeutic strategies that could open new avenues for the treatment of patients with MCL.

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Figure 1: Cell cycle and DNA damage response pathway dysregulation in MCL.
Figure 2: Schematic diagram representing the interplay between programmed cell death mechanisms and altered pathways in MCL.
Figure 3: Proposed model of molecular pathogenesis in the development and progression of MCL.

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Acknowledgements

We gratefully acknowledge M. Pinyol, L. Hernandez, S. Bea, P. Perez-Galan, G. Roue and the rest of the members of our group for critical feedback and thoughtful discussions. We acknowledge A. Rosenwald and G. Ott from the University of Würzburg and our colleagues from the European Mantle Cell Network, the Mantle Cell Consortium from the Leukemia Research Foundation and the Leukemia/Lymhoma Molecular Profiling Project for the continuous collaboration on these projects, and S. Swerdlow from the University of Pittsburg for the picture of the indolent lymphoma in figure 3. We apologize to investigators whose work is not cited owing to space restrictions. Research work at our laboratory discussed in the paper was supported by Comisión Interministerial de Ciencia y Tecnología (CICYT) SAF 05-5,855 and 06-8,850, Redes Temáticas de Investigacion Cooperativa de Cáncer (RTICC) from the Instituto de Salud Carlos III, Generalitat de Catalunya (2005SGRO870), Lymphoma Research Foundation, and the European Union Contract LSHC-CT 2004-503,351.

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DATABASES

National Cancer Institute

mantle cell lymphoma

FURTHER INFORMATION

US National Clinical Trials Database

Mantle Cell Consortium of the Lymphoma Research Foundation

Glossary

Mantle zone

Area of the lymphoid follicles mainly composed of naive B cells.

Lymphoid follicles

Lymphoid aggregates that form in tissues in which the B lymphocytes are stimulated by antigens and the microenvironment to generate high-affinity antibodies.

Uniparental disomy

Inheritance of two copies of one parent's chromosome, or part of a chromosome, and no copies from the other parent in a diploid individual.

Nonsense-mediated mRNA decay pathway

Eukaryotic cellular mRNA surveillance mechanism that ensures the rapid degradation of mRNA transcripts containing premature termination codons.

DNA replication licensing factors

Group of proteins that act sequentially in order to assemble pre-replication complexes at DNA replication origins to ensure that DNA is not replicated more than once in a single cell cycle.

Akt

Serine-threonine kinase involved in the transduction of extracellular stimuli that regulate cell cycle progression, proliferation, cell growth, apoptosis and survival.

CHOP

A standard chemotherapeutic regimen based on the use of cyclophosphamide, doxorubicin, vincristine and prednisone.

CD20

Antigen present both in normal B lymphocytes and in cells from most B-cell disorders.

HyperCVAD

An intense standard chemotherapeutic regimen based on the CHOP combination but also including high doses of methotrexate and cytarabine.

BCL2 family proteins

Includes up to 25 members, which are classified according to their structure and function as anti-apoptotic (BCL2-like) or pro-apoptotic (multidomain BAX-like and 'BH3-only') proteins.

Synthetic retinoids

Derivatives of vitamin A that show various biological effects and are able to modulate the expression of BCL2 family member proteins.

HDACs

Histone deacetylases are enzymes that regulate chromatin structure and function through the removal of the acetyl group from the lysine residues of core nucleosomal histones.

Heat-shock proteins

(HSPs). Chaperones that guide normal protein folding, intracellular localization and proteolytic turnover of many key cell growth, differentiation and survival regulators. Normally activated under stress conditions, HSPs also work as biological buffers of genetic lesions present in tumour cells, allowing them to increase their oncogenic potential.

Mitotic index

Number of mitoses observed at high power magnification in the microscopic examination of the tumour.

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Jares, P., Colomer, D. & Campo, E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 7, 750–762 (2007). https://doi.org/10.1038/nrc2230

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