Molecular Pathogenesis of Mantle Cell Lymphoma: New Perspectives and Challenges With Clinical Implications
Section snippets
Initial Oncogenic Steps and Cell of Origin
The t(11;14)(q13;q32) is considered the primary oncogenic event in MCL. This translocation juxtaposes the CCND1 gene on 11q13 to the IGH gene on chromosome 14 leading to the overexpression of cyclin D1 that is not usually expressed in normal B cells. This translocation occurs at the pre-B stage of differentiation during the recombination of the V(D)J segments of the IGH gene in the bone marrow.3 Although the initial oncogenic translocation is acquired in an immature B cell, the tumor is
Cyclin D1 Overexpression: Cell Cycle Deregulation and Beyond
The t(11,14)(q13,q32) translocation is virtually present in all MCL and deregulates constitutively cyclin D1. The main form of cyclin D1 expressed in these tumors is a 36-kd polypeptide (isoform a) encoded by two main transcripts of 4.5 and 1.5 kb with different length of the 3′ untranslated region (UTR). The shorter transcript lacks the terminal 3′UTR that contains AU-rich elements involved in transcript instability and binding sites for different miRs (miR-16, miR-503, miR-15a, miR-34a,
Cyclin D1–Negative Mantle Cell Lymphoma
The detection of cyclin D1 overexpression due to the t(11;14) translocation in MCL is a hallmark for the diagnosis of this entity. However, a small subset of tumors with the morphology and phenotype of conventional MCL are negative for cyclin D1 expression and the t(11,14) translocation. Although the number of cases studied is still limited, the global gene expression profile and the portrait of secondary genetic alterations of these tumors are undistinguishable from those observed in cyclin
From Early Steps to Overt Lymphoma, a Long Latency Period
The oncogenic steps from the early event to the development of an overt lymphoma are not well known and may involve the acquisition of secondary genetic alterations and activation of additional pathways that facilitate the progression of the malignant clones. Interestingly, recent observations have suggested that this process may have a long latency and probably not all cells acquiring the initial translocation will evolve into a malignant lymphoma. Cells carrying the t(11;14) translocation
Secondary Genetic Alterations
Compared to other lymphomas, a high number of MCLs (93%) are genetically altered and have a high number of genomic aberrations per tumor.20, 31 The initial cytogenetics and metaphase comparative genomic hybridization (CGH) studies identified a complex profile of secondary chromosomal alterations involving recurrent gains in 3q, 6p, 7p, 8q, 10p13, 12q, and 18q, as well as losses of 1p, 6q, 8p, 9p, 9q, 10p14-p15, 11q14-q23, and 13q.20, 32 Regions involving gains of 3q, 7p, and 12q, and losses of
Pathogenetic Pathways Targeted by Genetic Alterations
Most genes targeted by recurrent chromosome abnormalities in MCL are elements of the cell cycle control, DNA damage and repair response, and cell survival pathways.1, 2 Interestingly, the refinement of the new genetic studies is expanding the number of genes involved in these mechanisms but is also revealing the potential implication of new pathways such as the Hippo signaling pathway44 and the network of microtubule-associated proteins.41
The fact that a G1 cyclin is the target oncogene of the
Pathways Constitutively Activated in MCL Without Apparent Genetic Alterations
Several signaling pathways implicated in cell growth and survival regulation are constitutively activated in MCL, although the primary mechanisms triggering this activation are not well elucidated (Figure 4). Understanding the deregulation of these pathways is increasingly relevant because new drugs targeting different elements are being developed with promising results in the clinics.
Indolent Non-nodal Mantle Cell Lymphomas: An Alternative Pathogenetic Pathway?
The common understanding of MCL as a very aggressive lymphoma with relative short survival of the patients and frequent requirement of an intensive therapy has led investigators to overlook a subset of patients that may follow an indolent clinical course even without chemotherapy for a long period of time. This indolent clinical evolution was recognized initially in patients presenting with splenomegaly and a leukemic non-nodal disease.6, 72 The relevance of identifying these patients at
Acknowledgments
The authors thank Dr Sílvia Beà and Dr Kostas Stamatoupoulos for their helpful comments on the manuscript. They also thank Dr Andreas Rosenwald, Dr German Ott, the European Mantle Cell Lymphoma Consortium, and the Mantle Cell Lymphoma Consortium from the Lymphoma Research Foundation for their continuous collaboration in the study of this lymphoma.
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51st American Society of Hematology Annual Meeting, New Orleans, LA
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2023, European Journal of Medicinal ChemistrySOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma
2017, BloodCitation Excerpt :Patients have short responses to current therapies and frequent relapses.1,2 However, recent studies have identified a subset of MCL with indolent clinical behavior that tends to present with leukemic disease instead of extensive nodal infiltration, and patients may not need chemotherapy for long periods of time.3-7 These cases have been recognized as “leukemic nonnodal MCL.”2
Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis
2013, Leukemia ResearchCitation Excerpt :These observations indicate that Mino and JeKo-1 cells responded differentially to the Ibrutinib mediation of cell death induction. One of the most important mechanisms contributing to the development of MCL is the overexpression of cyclin-D1 due to t(11;14)(q13;q32) chromosomal translocation that juxtaposes CCND1 proto-oncogene that is located at chromosome 11q13 next to the immunoglobulin heavy chain gene (IGH) region in chromosome 14q32 [20]. It is worth mentioning, however, that the overexpression of cyclin-D1 in lymphoid tissues fails to develop overt lymphoma, but mediates lymphoid hyperplasia.
Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma
2012, BloodCitation Excerpt :In addition to the t(11;14) translocation several secondary genetic events are necessary for lymphomagenesis,1,14-16 and some of these have been associated with clinical outcome. Features associated with worse prognosis include genetic aberrations that lead to further disturbances of cell cycle regulation, including truncation of the cyclin D1 transcript, mutation of genes involved in DNA damage response (deletions and mutations of ATM and/or TP53), and dysregulated cell survival pathways.17,18 CCND1 gene translocation and cyclin D1 nuclear protein expression are used for diagnostic purposes and distinguish MCL from other types of lymphomas.10
IV. Mantle cell lymphoma
2019, Japanese Journal of Cancer and Chemotherapy
Supported by Spanish Ministry of Science and Innovation SAF 2008-03630, Instituto de Salud Carlos III “Red Temática de Investigación Cooperativa de Cáncer” (2006RET2039), Instituto de Salud Carlos III “Beca Predoctoral de Formación en Investigación en Salud” (FI08/00437) and Ministry of Science and Innovation “Formación de Personal Investigador” (BES-2007-16330).