Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

Abstract

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma of which at least a subset arises from antigen-experienced B cells. However, what role antigen stimulation plays in its pathogenesis remains ill defined. The genetic hallmark is the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. Secondary genetic events increase the oncogenic potential of cyclin D1 and frequently inactivate DNA damage response pathways. In combination these changes drive cell-cycle progression and give rise to pronounced genetic instability. Several signaling pathways contribute to MCL pathogenesis, including the often constitutively activated PI3K/AKT/ mTOR pathway, which promotes tumor proliferation and survival. WNT, Hedgehog, and NF-B pathways also appear to be important. Although MCL typically responds to frontline chemotherapy, it remains incurable with standard approaches. Proteasome inhibitors (bortezomib), mTOR inhibitors (temsirolimus), and immunomodulatory drugs (lenalidomide) have recently been added to the treatment options in MCL. The molecular basis for the antitumor activity of these agents is an area of intense study that hopefully will lead to further improvements in the near future. Given its unique biology, relative rarity, and the difficulty in achieving long-lasting remissions with conventional approaches, patients with MCL should be encouraged to participate in clinical trials. (Blood. 2011; 117(1):26-38) Diagnosis, clinical course, and the origin of MCLMantle cell lymphoma (MCL), a mature B-cell neoplasm defined as a distinct entity in the early 1990s constitutes ϳ 6% of all non-Hodgkin lymphomas (NHLs). 1-4 MCL is typically disseminated at presentation, with a leukemic component in 20%-30% of patients. Classic and blastoid variants are recognized, the latter associated with inferior clinical outcome ( Figure 1A). The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to aberrant expression of cyclin D1, which is not typically expressed in normal lymphocytes ( Figure 1B). However, cyclin D1-negative cases having typical morphology and gene expression profile have been described and often show overexpression of cyclin D2 or D3. 5 Recently, SOX11 has been described as a diagnostic maker that is equally expressed in D1-positive and D1-negative MCL. 6,7 MCL is one of the most difficult to treat B-cell lymphomas. Although conventional chemotherapy induces high-remission rates in previously untreated patients, relapse within a few years is common, contributing to a rather short median survival of 5-7 years. 8,9 The best predictor of survival is tumor proliferation ( Figure 1C). 5 Intensification of first-line treatment has improved progression-free survival, but no curative regimen has been defined so far. 2,3 In MCL, as in chronic lymphocytic leukemia (CLL), the variable region of the expressed immunoglobulin heavy chain gene (IGHV) displays either germline configuration (Ig-unmutated), as found in naive B cells, or contains somatic mutations (Ig-mutated), indicat...

Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation

“…MCL cells also carry a high number of secondary genomic alterations involving key genes in cell-cycle control, DNA damage response, and survival pathways. 1,2 Tumor proliferation has emerged as the main determinant of survival. 3 MCL is one of the most difficult to treat B-cell lymphomas.…”

Nodal and leukemic small B-cell neoplasms

“…47 The cytogenetic hallmark of MCL is the t(11;14)(q13;q32) IGH/CCND1 translocation, which is identified in 495% of cases. [67][68][69] Variant translocations involving CCND1 may also occur in a minority of cases, such as those involving IGK or IGL loci. 70 CCND1 translocation results in overexpression of the Cyclin D1 protein, promoting cell cycle progression and proliferation.…”

The current therapeutic scenario for relapsed mantle cell lymphoma

“…Clinical guidelines, although recently updated [9 & ], are not specifically focused on the relapse setting, supplying only some hints. Moreover, the numerous new targeted options [2], along with the promising data for combinations with conventional chemotherapeutics and anti-CD20 immunotherapy, could generate hesitation about the optimal therapeutic approach for these patients. Thus, the present review focuses on the major therapeutic discoveries of the last few years to offer a practical algorithm to select appropriate treatment decisions in patients with relapsed MCL.…”

“…Most of the new targeted approaches available in the clinics or being tested in early phase I/II protocols result from recent molecular studies on cell proliferation and apoptosis pathways [2]. Moreover, ongoing molecular genetic investigations continue to identify new oncogenic targets, providing preclinical rationale for therapeutic application and further drugs development [3][4][5].…”