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Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Mantle cell lymphoma (MCL) is a molecularly intriguing malignancy in which the t(11;14)(q13;q32) translocation, associated with the cell cycle regulator CCND1 (11q13) and IGH locus (14q32), leads to the constitutive overexpression of cyclin D1. Cyclin D binds to CDK4/6 and causes cell cycle deregulation. It is proposed that this, together with the acquisition of genetic alternations in the BCR and other signalling pathways play a pivotal role in its lymphomagenesis. Two variants, based on the presence or absence of the transcription factor SOX11, and various mutations that affect DNA repair genes (ATM, CCND1 and TP53), epigenetic modifiers (WHSC1, MLL2, MEF2B, RB1, POT1 and SMARCA4A) have been described. Patients with clinically aggressive disease often have activating NOTCH 1/2 and BIRC3 mutations.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and B-Cell Prolymphocytic Leukemia
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
CLL with nuclear irregularities, especially indentation of the nuclear membrane (cleaved cells), requires differentiation from MCL (Figure 8.19). MCL differs from SLL/CLL by lack of CD23 and positive BCL1 (cyclin D1) expression (Figure 8.20). However, both disorders may display an aberrant phenotype (e.g., CD23− CLL, or CD23+ MCL), and therefore correlation with t(11;14)/CCND1 status is required for definite diagnosis. SOX11, a transcription factor regulating the neural development is positive in MCL and not in CLL. It is positive in MCL cases that are negative for cyclin D1 (BCL1). Absence of SOX11 in MCL confirmed by cyclin D1 expression and t(11;14) identifies an indolent subgroup of MCL [146,147]. Occasional CLL cases with atypia may mimic T-cell lymphoproliferations on cytologic examinations (Figure 8.21). FC immunophenotyping helps to establish the correct diagnosis in those cases.
Non-Hodgkin lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Piers Blombery, Adrian Bloor, David C. Linch
Mantle cell lymphoma (MCL) accounts for approximately 5%-10% of all cases of NHL. It is an aggressive NHL subtype occurring predominantly in older adults with a male predominance. MCL typically presents with advanced-stage disease. In the minority of patients with apparently localized disease by conventional staging, occult systemic disease is almost always present and can be identified by sensitive molecular methods or extended staging investigations (e.g., biopsies of macroscopically uninvolved colonic mucosa). The pathological hallmark of MCL is the overexpression of cyclin D1 leading to cell-cycle dysregulation which, in the vast majority of cases, is due to a translocation between the CCND1 locus (encoding cyclin D1) on chromosome 11q13 and the immunoglobulin heavy chain enhancer-promoter on chromosome 14q32 (t(11;14)). Nuclear overexpression of cyclin D1 can be detected by immunohistochemistry on lymph node or trephine specimens. Alternatively, the t(11;14) can be detected by fluorescence in situ hybridization (FISH) or by PCR amplification of the translocated region. Histologically, the majority of cases of MCL are composed of small- to medium-sized mature appearing lymphocytes (classic MCL); however, in approximately 5% of cases the lymphocytes are more primitive appearing (blastoid or pleomorphic variants). Histological variants with primitive morphological features are associated with higher rates of CNS involvement and are independently associated with a poorer prognosis. A minority of patients present with a lower tumour burden, typically with splenomegaly, and involvement of the peripheral blood. Pathologically these cases have been found to be characterized by absent SOX11 expression (a transcription factor that is expressed in almost all cases of classic MCL) and may have a more indolent course.
Exploiting gene mutations and biomarkers to guide treatment recommendations in mantle cell lymphoma
Published in Expert Review of Hematology, 2021
SOX11 (SRY-Box Transcription Factor 11) is a neural transcription factor involved in tissue remodeling during embryogenesis. It has now been recognized as a key transcription factor in the pathogenesis of MCL [40]. SOX11 is not expressed in most lymphoid neoplasms, except lymphoblastic lymphoma and T-prolymphocytic leukemia, both clear distinct entities from MCL. The overexpression of SOX11 has been demonstrated to be characteristic of MCL independent of CCND1 positivity, suggesting arole for SOX11 expression in the diagnosis of t(11;14)-negative cases. SOX11 contributes to the pathogenesis of MCL by the constitutive activation of PAX5, a master regulator of B-cell development that blocks terminal B-cell differentiation and promotes tumor growth. Furthermore, it suppresses BCL6 and induces angiogenesis through PDGFA, thus promoting tumor cell migration, adhesion, and proliferation. SOX11 expression in MCL is usually associated with poor outcomes, while SOX11 negative cases are typically seen in the non-nodal leukemic phase MCL. The complex mechanisms underlying the dysregulation of SOX11 in MCL are not fully understood yet, but they may involve epigenetic changes with three-dimensional DNA reconfiguration bringing a distant enhancer region close to the SOX11 promoter [41].
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
Several of the currently approved anti-lymphoma agents including temsirolimus, lenalidomide or bortezomib have at least partial anti-angiogenic activity [171–173]. Microvessel density (MVD) in pre-therapeutic extramedullary MCL samples of 177 patients positively correlated with MCL international prognostic index (MIPI) and had negative prognostic impact on survival [174]. Transcription factor SOX11 was shown to be a key driver of proangiogenic signals in MCL [175,176]. Addition of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, to R-CHOP immunochemotherapy did not significantly improve patient outcome compared to historical controls [177]. The role of angiogenesis and potential anti-angiogenic treatment approaches with tyrosine-kinase inhibitors, e.g. imatinib or sorafenib, remain a domain of preclinical investigation [178].
Novel agents for mantle cell lymphoma: molecular rational and clinical data
Published in Expert Opinion on Investigational Drugs, 2020
Clémentine Sarkozy, Vincent Ribrag
Mantle cell lymphoma (MCL) is an aggressive B cell non-Hodgkin lymphoma (NHL) characterized by the presence of the translocation t(11;14)(q13;q32) [1]. Although the presumed cell of origin (COO) is a naïve pre-germinal center B cell, yet not exposed to the germinal center (GC) reaction, the restriction in immunoglobulin (IG) repertoire observed in MCL suggests an antigen-driven process [2]. Based on a distinct clinical presentation, outcome, and molecular features, a group of ‘non-nodal MCL’ has been described and recently accepted in the WHO classification as a definite entity [3] with a distinct COO that experienced a GC reaction. Indeed, these non-nodal MCLs present a memory B cell methylation signature as opposed to the classical or nodal MCL that carries a naïve signature [4]. SOX11 transcription factor expression, that prevents the lymphoma B cell to enter in GC reaction, is one of the key features that distinguishes nodal forms from the indolent and also from other NHL, usually SOX11 negative [5]. CCND1 overexpression, as a consequence of the t(11;14), is a key founder but other events are needed to acquire the full malignant phenotype in MCL, characterized by the accumulation of complex abnormalities. Among the most recurrent: ATM and TP53 alterations make of MCL an entity with a high enprint of DNA damage [6].