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Review
. 2011 Jan 6;117(1):26-38.
doi: 10.1182/blood-2010-04-189977. Epub 2010 Oct 12.

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

Patricia Pérez-Galán  1 , Martin Dreyling, Adrian Wiestner
Affiliations
Review

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

Patricia Pérez-Galán et al. Blood. .

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-κB 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.

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Figures

Figure 1
Figure 1
Clinical and biologic characteristics of MCL. (A) MCL diagnosis is based on morphology and immunophenotyping (CD20+, CD5+, CD23−, FMC7+). Pathologic subclassification recognizes 2 main subsets: classic and blastoid. (B) Fluorescence in situ hybridization (FISH) cytogenetics showing translocation t(11;14)(q13;q32) and immunohistochemistry for detection of cyclin D1 overexpression are helpful adjuncts in the diagnosis of MCL. Immunohistochemistry images provided by Stefania Pittaluga; images of FISH testing provided by Diane C. Arthur. (C) Tumor proliferation determines outcome. Figure adapted from original with permission. The expression levels of 20 genes related to cell proliferation were summarized in the proliferating signature average. Lowest (green) to highest (red) expression of the proliferation signature average in lymph node biopsies from 92 patients with MCL is shown with across a 16-fold range. Kaplan-Meier analysis for patients grouped into 4 quartiles on the basis of this score is shown. (D) CCND1 locus at 11q13 and cyclin D1 mRNA isoforms. Shaded boxes represent coding sequences, open boxes represent noncoding exon sequences. The 3′UTR of full-length 4.5-kb cyclin D1a contains binding sites for miRs (blue boxes) and AU-rich elements (red triangles); cyclin D1a isoforms with a truncated 3′UTR lack these elements. The alternatively spliced 1.7-kb cyclin D1b mRNA lacks exon 5 and retains part of intron 4. Illustration by Paulette Dennis.
Figure 2
Figure 2
Cyclin D1, at the center of MCL pathogenesis. Cyclin D1 mRNA stability and translation is increased by the PI3K/AKT/mTOR pathway. Cyclin D1 translocates into the nucleus and forms a holoenzyme with CDK4/6 to phosphorylate the retinoblastoma protein (RB), resulting in the release of E2F transcription factors and G1/S phase transition. In addition, cyclin D1/CDK4 complexes have kinase-independent functions, notably binding of the cell-cycle inhibitor p27kip, which is thereby titrated away from cyclinE/CDK2 complexes further promoting cell-cycle progression. Cyclin D1/CDK4 inhibits degradation of CDT1, the rate-limiting factor in DNA replication. Stabilization of CDT1 in S phase can induce the replication of already transcribed chromosomal segments, giving rise to increased numbers of double strand breaks and activation of DNA damage checkpoints. In S phase cyclin D1 is phosphorylated on threonine 286 by GSK3β, exported from the nucleus by CRM-1, polyubiquitinated by the E3 ligase SCF(FBX4-αB Crystallin), and degraded through the proteasome (reviewed in Kim and Diehl ). GSK3β is phosphorylated and inactivated by AKT and WNT signaling. Several components of this cell-cycle control machinery are altered in MCL: blue symbols (Δ) indicate molecules inactivated or down-regulated; red symbols, molecules activated or overexpressed. Illustration by Paulette Dennis.
Figure 3
Figure 3
Defective DNA damage responses in MCL. DNA damage activates the kinases ATM and ATR, together with p53 and p14/ARF, which can induce cell-cycle arrest, DNA repair, or apoptosis. The E3-ubiquitin ligase MDM2 that targets p53 for proteasomal degradation is inhibited by ARF, which in turn is inhibited by BMI1. CHK1 and CHK2, activated by ATR and ATM, respectively, phosphorylate key substrates (p53, CDC25A, CDC25B), leading to cell-cycle arrest. Several steps in this DNA damage response are altered in MCL: blue symbols (Δ) indicate molecules inactivated or down-regulated; red symbols, molecules activated or overexpressed. Illustration by Paulette Dennis.
Figure 4
Figure 4
BCR, NF-κB, and PI3K/AKT/mTOR deregulation in MCL. BCR engagement induces SYK phosphorylation, which in turn activates phospholipase C-γ (PLC-γ) and protein kinase C-β (PKC-β). PI3K functions as a transducer of BCR signaling and can be activated by SYK-dependent phosphorylation of CD19 and B-cell PI3K adaptor protein (BCAP). PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) on the plasma membrane to generate the second messenger, phosphatidylinositol-3,4,5-trisphosphate (PIP3). This process is reverted by PTEN. PI3K then phosphorylates PDK1 and the serine/threonine kinase AKT (Thr308) that activates mTOR (by inactivation of the inhibitor TSC1/2) and NF-κB (by activation of IKK). Only the mTOR complex 1 (mTORC1) is under AKT control and activates cap-dependent translation through S6K and 4E-BP1. mTOR complex 2 (mTORC2) can phosphorylate AKT (Ser473), increasing its kinase activity. Canonical NF-κB activation through AKT, or PKC-β involves IKK-mediated phosphorylation of the inhibitor IκBα, resulting in its proteasomal degradation and release of bound transcription factors that can then translocate to the nucleus. A20 and FAF1 inhibit NF-κB activation. The alternative pathway is activated by phosphorylation of p100 by IKKα complexes and subsequent proteasomal generation of p52. The cytokine BAFF/BLyS by binding to BAFF-R activates both canonical and noncanonical pathways. NF-κB transcription factors form heterodimers and homodimers to activate the transcription of genes involved in survival, proliferation, and apoptosis. Several steps in these signaling pathways are altered in MCL; blue symbols (Δ) indicate molecules inactivated or down-regulated; red symbols, molecules activated or overexpressed. Illustration by Paulette Dennis.
Figure 5
Figure 5
Activation of WNT and hedgehog pathways in MCL. (A) In the absence of WNT ligand, β-catenin is actively degraded through a protein complex called the “destruction box,” where GSK3β phosphorylates β-catenin, targeting it for degradation by the proteasome. Binding of WNT to Frizzled (FZD)– low density lipoprotein receptor-related protein (LRP) receptor complexes at the membrane, induces the formation of Dishevelled (DVL)–FZD complexes that sequester Axin and GSK3β, inhibiting the formation of the destruction box. This allows translocation of β-catenin to the nucleus where it dimerizes with TCF and LEF. (B) Binding of SHH to patched (PTCH), allows smoothened (SMO) to transduce a signal into the cytoplasm that leads to the breakdown of a protein complex formed by Fused, SUFU, and the transcription factor GLI. GLI is thereby released and translocates into the nucleus. Red symbols indicate molecules activated or overexpressed in MCL. Illustration by Paulette Dennis.
Figure 6
Figure 6
The antiapoptotic phenotype and alterations in BCL-2 family members in MCL. The prosurvival BCL-2 family members (BCL-2, BCL-XL, MCL-1, BCL-W, and A1/BFL1) bind and sequester the apoptosis-inducing members BAX and BAK. The BH3-only proteins (BIM, PUMA, NOXA, BAD, BID, BMF, BIK, and HRK) can be activated by cytotoxic signals and selectively engage prosurvival members, which leads to release of BAX and BAK, leading to permeabilization of the mitochondrion, the release of proapoptotic factors, caspase activation, and, finally, cell death., BCL2L11/BIM is frequently deleted (blue symbol [Δ]), whereas some antiapoptotic family members are commonly overexpressed (red symbols) in MCL, including BCL-2. In addition, PI3K/AKT/mTOR signaling can inactivate BAD through phosphorylation and stabilize of MCL-1 protein. Illustration by Paulette Dennis.
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