Molecular pathogenesis of mantle cell lymphoma

Abstract

Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients.

Figure 1. Hypothetical models of two different molecular subtypes of MCL.

The naive B cell carrying the t(11;14) colonizes the mantle zone of the lymphoid follicle and generates an in situ MCL lesion. Most MCLs evolve from these cells or cells in the marginal zone with no or limited IGHV somatic mutations. These tumors express SOX11, are genetically unstable, and tend to accumulate alterations in genes dysregulating cell cycle, DNA damage response pathways, and cell survival mechanisms. Alternatively, some cells with the t(11;14) may enter the germinal center and undergo IGHV somatic hypermutations. These cells are genetically stable and do not express SOX11. The tumors derived from these cells tend to spread to the peripheral blood and spleen more than to lymph nodes. The disease seems to be stable for long periods of time, but some of these tumors may acquire mutations in genes such as TP53 that lead to disease progression. Intriguingly, some tumors with the pathological and genetic features of MCL do not carry translocations of the CCND1, CCND2, and CCND3.

Figure 2. Major aberrant pathways in MCL susceptible to targeted therapies.

Numerous signaling pathways are constitutively activated and/or deregulated in MCL, including BCR, BAFF-R, mTOR, WNT, and NOTCH1 signaling as well as pathways that promote the cell cycle and inhibit apoptosis. mTOR and proteasome inhibitors are the only two pathways for which specific drugs have been approved. Several small molecules targeting the BCR and the PI3K/AKT/mTOR pathway at different levels (indicated by white text) are currently being studied in clinical trials. Other clinical trials are using small molecules to target the BCL2 family proteins directly involved in apoptosis and the cyclin-dependent kinases (CDKs) directly involved in the progression through G₁/S and G₂/M phases of the cell cycle. The WNT and NOTCH1 pathways are potential targets for β-catenin (β-cat) inhibitors and NOTCH1 inhibitors, respectively. Pharmacologic inhibition of PARP activity has become an interesting therapeutic strategy in tumors with dysfunctional DNA repair mechanisms, such as MCL.

Figure 3. Multistep model in the progression of MCL.

Clonal cells carrying the t(11;14) translocation may be detected in the peripheral blood of healthy individuals at very low levels. The risk of progression of these clones must be extremely low, if any. Cells expressing cyclin D1 and carrying the t(11;14) may be found in the mantle zone of lymphoid follicles in otherwise reactive tissues. Most of these lesions will not evolve into an overt lymphoma. The incidental detection of tumor cells in the mantle zone of reactive tissues in patients with MCL who appear to be in complete remission suggests that this microenvironment may sustain chemoresistant cells. Anecdotal clinical observations provide a timeframe for the potential evolution of these lesions. Original magnification, ×100 (right and left), ×400 (center).