• mantle cell lymphoma;
  • cyclin D1;
  • cell cycle;
  • DNA damage


  1. Top of page
  2. Summary
  3. Conclusion
  4. Acknowledgements
  5. References

Mantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 that may show a spectrum of morphological and phenotypic features broader than initially described. Although some patients may follow an indolent clinical evolution, in most of them the tumour has an aggressive behaviour with poor response to conventional chemotherapy. The genetic hallmark is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which is considered the initial oncogenic event. In addition to this translocation, MCL may carry a high number of secondary chromosomal and molecular alterations that target regulatory elements of the cell cycle machinery and senescence (BMI1/INK4/ARF/CDK4/RB1), DNA damage response pathways (ATM/CHK2/p53), and cell survival signals. The knowledge of these mechanisms and their influence on the behaviour of the tumour are facilitating the development of prognostic models with a more precise prediction of the clinical evolution of the patients. This information coupled with the availability of a new generation of innovative drugs targeting basic molecular process of the tumour cells, should facilitate the design of new therapeutic protocols able to overcome the resistance of this aggressive lymphoma to conventional treatments and improve the life expectancy of the patients.

Mantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm characterized by a proliferation of mature B-lymphocytes that have a remarkable tendency to disseminate (Swerdlow et al, 2001). This tumour is considered one of the most aggressive lymphoid neoplasms with poor responses to conventional chemotherapy and relatively short survival. MCL was initially identified based on its particular histological and phenotypic characteristics but the overlapping features with other similar lymphoid neoplasms made difficult its diagnosis. The identification of the t(11;14)(q13,q32) translocation, deregulating CCND1 as the specific genetic alteration of this lymphoma, has enabled a more precise identification of the entity, which in turn has facilitated the recognition of a broader spectrum of clinical and pathological manifestations and a better understanding of the pathogenetic mechanisms and natural history of the disease. This review will examine the more recent advances in understanding this tumour from the clinical and pathological aspects to the new perspectives in the genetic and molecular mechanisms of the disease.


The MCL represents approximately 4–10% of all cases of non-Hodgkin lymphoma (NHL). It occurs primarily among elderly individuals with a median age of approximately 60 years (range 29–85). This tumour has a male predominance with a male: female ratio around 2–7:1. Similar to chronic lymphocytic leukaemia (CLL) and other lymphoid neoplasms, occasional cases of MCL have been observed in families in which a first-degree relative developed a MCL or other lymphoid malignancies (Tort et al, 2004). The neoplasm in the second generation tends to appear at an earlier age than in the parents, suggesting a genetic predisposition. Genetic studies in MCL patients have identified certain single nucleotide polymorphism (SNP) of the AURKA, TNFRSF10A and TNFRSF10B genes at higher frequency in MCL patients than in healthy controls, but the number of samples examined was limited (Fernandez et al, 2004; Camacho et al, 2006). Mutations in genes of the DNA damage response pathway such as ATM and CHEK2 have been detected in the germline of some patients with MCL, suggesting that alterations in this pathway may play a predisposing role in the development of the disease (Camacho et al, 2002; Hangaishi et al, 2002; Tort et al, 2002).

Cellular origin and normal cell counterpart

The t(11;14)(q13;q32) is considered the primary genetic event in the pathogenesis of the tumour (Campo et al, 1999). The analysis of the breakpoint regions has suggested that this translocation occurs in the bone marrow in an early B-cell at the pre-B stage of differentiation initiated by the recombination of the Ig gene V(D)J segments (Welzel et al, 2001). The distribution of tumour cells surrounding germinal centres and the expression of several genes normally detected in naïve and normal follicular mantle zone B cells have supported the relationship of this tumour to cells of the primary lymphoid follicle or the mantle cells of secondary follicles. In addition to this topographic distribution, the tumour cells co-express the T-cell associated antigen CD5. Normal CD5 positive B lymphocytes are a small subpopulation of naïve B cells that is present in fetal blood and decreases with age. These cells produce low affinity polyreactive antibodies, colonize the normal mantle zone of the lymphoid follicles and tend to recirculate (Dono et al, 2004). The similar phenotype and topographic distribution suggest that these cells may be the normal counterpart of MCL cells. All these observations indicate that, although the initial t(11;14) translocation occurs in an immature bone marrow B-cell, the selective oncogenic advantage of this chromosomal aberration fully develops when these cells attain the differentiation stage of a mature naïve pregerminal centre B-cell.

Somatic hypermutations in immunoglobulin variable region heavy chain (IGHV) genes are detected in 15–40% of MCLs indicating that some tumours originate in cells that have undergone the influence of the mutational machinery of the follicular germinal centre. A biased use of IGHV3-21, IGHV3-23 and IGHV4-34 has been detected in MCL, suggesting that these tumours may originate from specific subsets of B cells (see references in Table I). The rate of mutations in MCL is lower than in other lymphoid neoplasms, such as CLL or follicular lymphoma (Table I), suggesting a weaker influence of the germinal centre microenvironment. In contrast to CLL, tumours with IGHV3-21 mainly occur in unmutated MCL, show a tendency to have longer survival (Camacho et al, 2003; Kienle et al, 2003), and seem to have less genomic imbalances (Thelander et al, 2005). The mutational status of the IGHV genes in MCL does not correlate with survival or ZAP-70 expression (Kienle et al, 2003; Carreras et al, 2005). Interestingly, MCL with a leukaemic, non-nodal clinical presentation that are associated with a longer survival, have frequent mutated IGHV genes (Orchard et al, 2003).

Table I.   Percentage of somatic mutation in V gene sequences of IGHV genes in mantle cell lymphomas compared to chronic lymphocytic leukaemia.
ReferencesNo. of cases Unmutated >98%* Mutated <98%*Highly mutated <96%*
  1. *Degree of sequence homology with the germline gene.

Mantle cell lymphoma530391 (74%)139 (26%)49 (9%)
Hummel et al (1994)66 (100%)  
Pittaluga et al (1998)96 (67%)3 (33%)1 (11%)
Nakamura et al (1999)1311 (85%)2 (15%)1 (8%)
Thorselius et al (2002)5141 (80%)10 (20%)1 (2%)
Camacho et al (2003)9668 (71%)28 (29%)13 (14%)
Kienle et al (2003)141100 (71%)41 (29%)8 (6%)
Walsh et al (2003)11092 (84%)18 (16%)3 (3%)
Orchard et al (2003)6543 (66%)22 (34%)16 (25%)
Babbage et al (2004)1811 (61%)7 (39%)4 (22%)
Cogliatti et al (2005)2113 (62%)8 (38%)2 (10%)
Chronic lymphocytic leukaemia508271 (53%)237 (47%)199 (39%)
Hamblin et al (1999)8438 (45%)46 (55%)36 (43%)
Hultdin et al (2003)6134 (56%)27 (44%)16 (26%)
Crespo et al (2003)5635 (63%)21 (37%)18 (32%)
Rassenti et al (2004)307164 (53%)143 (47%)129 (42%)

Morphological and phenotypic characteristics

A better definition of the disease has expanded our knowledge of the morphological spectrum and the phenotypic variations of this tumour (Swerdlow et al, 2001). MCL cells in the lymph nodes adopt a mantle zone, nodular, or diffuse growth pattern, which might represent different stages of tumour infiltration. The mantle zone growth pattern may be difficult to distinguish from follicular or mantle cell hyperplasia and is characterized by an expansion of the follicle mantle area by neoplastic cells surrounding reactive germinal centres. This pattern is usually seen in areas of partially involved lymph nodes that otherwise show the most common nodular or diffuse involvement by the tumour. The observation of this pattern in isolated lymph nodes of occasional patients with an indolent clinical course (Nodit et al, 2003; Espinet et al, 2005), suggest that it represents the initial infiltration of the follicle by the tumour cells. MCL cyclin D1 staining has revealed that not uncommonly the tumour cells infiltrate the germinal centre of the follicles. These cells may totally replace the lymphoid follicle leading to the nodular pattern that may retain a meshwork of follicular dendritic cells. Later in the course of the disease, invasion and obliteration of internodular areas by neoplastic cells results in a diffuse pattern of growth that it is the more commonly observed in MCL.

The MCL has two major cytological variants that are associated with different biological and clinical characteristics, the classic variant occurs in 80–90% of cases and the blastoid variant is present in 10–20% of patients. The classical cytological appearance of MCL is a monotonous proliferation of small/medium cells with irregular nuclei and inconspicuous nucleoli. Some tumours may show small cells with round nuclei mimicking CLL but in these cases the cells do not have the characteristic central nucleoli of the prolymphocytes and paraimmunoblast present in the latter entity. Interestingly, this cytological variant has been frequently recognized in patients with a leukaemic and splenomegaly presentation without lymph nodes and a more indolent clinical course (Angelopoulou et al, 2002; Orchard et al, 2003). Although MCL proliferation activity may vary from case to case, it is generally low, with Ki-67 positive cells around 15–30%. The two cytological variants identified as classic blastoid and pleomorphic MCL in the current World Health Organization (WHO) classification are associated with more aggressive clinical evolution. Classic blastoid MCL show an extremely high proliferative activity with numerous mitotic figures, high percentage of Ki-67 positive cells (>40%), and sometimes a ‘starry sky pattern’ similar to Burkitt’s lymphoma. Pleomorphic MCLs are composed of a more heterogeneous population of larger cells. Although the proliferation activity is high it is usually lower than in blastoid cases. These tumours are frequently tetraploid and it is not uncommon to observe mitotic figures highly hyperchromatic with an apparent high number of chromosomes (Ott et al, 1997). These cytological variants represent the ends of a morphological spectrum and transitional forms between them may be observed in some tumours in which it may be difficult to decide whether the cytology is classical, blastoid, or pleomorphic (Tiemann et al, 2005). Some tumours may have very discordant morphology with areas of pleomorphic cells intermingled with others with a classical morphology (Fig 1).


Figure 1.  MCL with discordant morphology. (A) Mantle cell lymphoma with a mixed population of classical small tumour cells with irregular nuclei on the left side of the picture and a pleomorphic component of larger cells and abundant mitosis on the right. Original magnification ×100. (B) Cyclin D1 staining is overexpressed in both components confirming the diagnosis of MCL with a classical and pleomorphic component in the same tumour (Courtesy of Dr U Zanetto, City Hospital, Birmingham, UK). Original magnification ×200.

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Blastoid variants occur usually de novo and less frequently in patients with previous diagnosis of classical MCL (Norton et al, 1995; Argatoff et al, 1997). Recent data supports the view that blastoid MCL arising in patients with previous diagnosed classical MCL represents histological transformation of the initial neoplastic clone rather than a de novo tumour (Yin et al, 2007).

The phenotype of MCL is relatively characteristic with expression of mature B-cell antigens and co-expression of the T-cell associated antigens CD5 and CD43. The IgM/IgD surface immunoglobulins are usually intense and frequently associated with the lambda light chain, and CD23 is generally negative. Some MCL may show phenotypic variants that may make the diagnosis difficult. Thus, some tumours may be CD5 negative, particularly among blastoid variants, and dim CD23 may be detected by flow cytometry in a number of cases (Gong et al, 2001; Schlette et al, 2003). Detection of CD8 and CD7 by flow cytometry has been reported in isolated cases of MCL (Hoffman et al, 1998). MCL is usually negative for the follicular germinal centre markers BCL6, CD10, and the plasma cell differentiation antigen MUM1 but expression of these antigens have been detected in occasional cases (Camacho et al, 2004). The clinical and biological significance of these phenotypic variants is currently unclear.

The t(11;14)(q13;q32) translocation and cyclin D1 deregulation

The t(11;14)(q13;q32) translocation is the genetic hallmark of MCL. This translocation is detected by conventional cytogenetics in up to 65% of MCLs. However, using different fluorescent in situ hybridization (FISH) techniques, it can be found in virtually all cases of MCL (Vaandrager et al, 1996). This translocation involves the immunoglobulin heavy chain gene (IGH) at 14q32 locus and a region at 11q13 designated BCL-1 (Fig 2). The majority of breakpoints sites at 11q13 occur in a region named the major translocation cluster (MTC). CCND1, encoding cyclin D1, is the closest gene located 120 kb downstream of the MTC locus, and its expression is deregulated by the translocation. Although normal B lymphocytes might express cyclin D2 and D3 (Teramoto et al, 1999), cyclin D1 is not normally expressed in these cells, but it is overexpressed at both mRNA and protein levels in MCL (Bosch et al, 1994; de Boer et al, 1995).


Figure 2.  The translocation t(11;14)(q13;q32) in MCL. (A) Schematic representation of the germline immunoglobulin heavy chain (IgH) locus (IGH@) on chromosome 14q32 displaying the genomic organization of the variable (V), diversity (D), joining (J) and the constant region (only the Cμ gene is shown). The breakpoint in IGH seems to occur between the diversity and joining regions during the early steps of the V(D)J recombination. (B) Genomic organization of the BCL-1 (B-cell lymphoma/leukaemia 1) locus on chromosome 11q13. The majority of breakpoints (30–50%) happen at the major translocation cluster (MTC), however there is some variability and 10–20% of the breaks occurs outside the MTC closer to CCND1. (C) The translocation leads to a 5′-5′ fusion of the bcl-1 locus with sequences from the IGH@ locus and brought under the control of the IgH enhancer, CCND1. Sizes of exons and intermediate DNA segments are not to scale.

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Cyclin D1 cloning identified two transcripts of approximately 4·5 and 1·5 kb. Both transcripts contain the whole coding region that codify for a 36 kDa polypeptide (isoform a), but differ in the length of the 3′ untranslated region (UTR) (Xiong et al, 1991), that contains an AU-rich element involved in transcript instability (Seto et al, 1992). Some MCL lack the long mRNA transcript but overexpress shorter cyclin D1 transcripts missing the AU destabilizing elements. These shorter transcripts are generated by secondary 3′ rearrangement in the CCND1 locus (Bosch et al, 1994; de Boer et al, 1997), or by genomic deletions and point mutations at the 3′UTR (Wiestner et al, 2007). Although the role that these shorter transcripts could have in MCL is not clear, its expression correlates with high levels of CCND1 mRNA, increased proliferation, and poor survival of the patients (Rosenwald et al, 2003; Sander et al, 2005; Wiestner et al, 2007), suggesting that these secondary events in the 3′ region of the gene may be important in the progression of the disease.

CCND1 also encodes for a less abundant isoform protein generated by an alternative splicing (isoform b) (Betticher et al, 1995). Interestingly, this isoform has been related to a common SNP (G/A 870) that seems to modulate the splicing process of cyclin D1 (Howe & Lynas, 2001). Although this SNP has been associated with increased cancer risk or poor outcome in different tumours (Knudsen et al, 2006), it does not seem to have an impact in MCL (Carrere et al, 2005). In addition, despite the evidences suggesting the tumorigenic role of this isoform (Solomon et al, 2003), its implication in MCL pathogenesis is not clear since human MCL cells mostly express the canonical cyclin D1a isoform and only low levels of the cyclin D1b mRNA (Marzec et al, 2006).

Cyclin D1 negative MCL

The MCL expression profile analysis has identified rare tumours that, despite being negative for cyclin D1 and the t(11,14), showed a morphology, phenotype, and global expression profile undistinguishable from conventional MCL. These cases seem to have a clinical behaviour and a secondary genetic alteration profile similar to conventional MCL suggesting that they correspond to the same disease. However, only a few of these cases have been reported (Fu et al, 2005; Salaverria et al, 2007). Interestingly, these cases have high expression of cyclin D2 or D3. Although the mechanism deregulating these cyclins is not well understood, a recent report has identified cases carrying a t(2;12)(p12;p13) translocation fusing CCND2 to the kappa light Ig chain gene locus (IGK@) (Gesk et al, 2006). This data suggest that deregulation of other cyclins may be an alternative mechanism to cyclin D1 overexpression in MCL tumorigenesis.

The recognition of this MCL cyclin D1-negative variant in routine practice is challenging. Some small B-cell lymphomas, such as marginal zone lymphomas, follicular lymphomas, or small lymphocytic lymphomas, may mimic MCL both morphologically and phenotypically. The differential diagnosis between these tumours and a cyclin D1-negative MCL may be relevant for patient management. Unfortunately, the only reliable criteria to establish the diagnosis of cyclin D1 negative MCL seems to be the microarray profile that it is limited to research environments. The immunohistochemistry detection of cyclin D2 or D3 may not be helpful because these cyclins are also expressed by other types of lymphomas. However, the array study has shown significant higher levels of these cyclins in cyclin D1 negative MCL than in other lymphomas. Therefore, the development of quantitative assays (e.g. qPCR) for the detection of these cyclins may be useful in this differential diagnosis.

How does cyclin D1 contribute to MCL lymphomagenesis?

Cyclin D1 plays an important role in the cell cycle regulation of G1-S transition following mitotic growth factor signalling. Cyclin D1 binds to CDK4 and CDK6 to form a CDK/cyclin complex able to phosphorylate the tumour suppressor gene retinoblastoma (RB1) facilitating cell cycle progression. RB1 plays a master role in the G1-S transition by sequestering and inactivating E2F transcription factors involved in the transactivation of essential genes required for S phase entry and DNA replication, including cyclin E (Harbour & Dean, 2000). The initial phosphorylation of RB1 by cyclin D1/CDK4-6 will initiate the release of E2F transcription factors promoting the accumulation of Cyclin E/CDK2 complexes that will produce the irreversible inactivation of RB1 and the subsequent progression into S phase (Fig 3). Thus, cyclin D1 overexpression would contribute to the lymphomagenesis in MCL by overcoming the suppressor effect that retinoblastoma performs in the G1/S transition. In that sense, RB1 seems to be normally expressed in the majority of MCL cases and the protein appears to be hyperphosphorylated (Zukerberg et al, 1996), particularly in highly proliferative blastic variants (Jares et al, 1996).


Figure 3.  Potential role of cyclin D1 in G1/S phase transition. Cyclin D1 binds to CDK4 and controls the G1/S-phase transition by initiating the hyperphosphorylation of RB1 allowing the accumulation of cyclin E. In addition, the titration of p27 into cyclin D1/CDK4 complexes will promote the raising of active cyclin E/CDK2 complexes that will enhance p27 degradation and further phosphorylation of RB1 allowing the cell to progress into S phase.

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The different CDK/cyclin complexes are tightly regulated by the action of two families of CDK inhibitors. The INK4 family is specific for CDK4/6. However, the Cip/Kip family, which includes p27 among others, shows a broad CDK inhibition activity targeting all the different CDK/cyclin complexes (Sherr & Roberts, 1999). Moreover, the Cip/Kip proteins appear to have an important role in the formation of active CDK4/cyclin D complexes (LaBaer et al, 1997). This property seems to be responsible for the p27 titration into CDK4/cyclin D1 complexes by deregulated cyclin D1, preventing the p27-dependent inactivation of CDK2/cyclin E and G1 cell cycle arrest. Moreover, the presence of active CDK2/cyclin E complexes will phosphorylate p27, targeting it for ubiquitination and proteosome degradation allowing cell cycle progression (Montagnoli et al, 1999) (Fig 3). In NHL other than MCL, p27 protein expression is inversely related to the proliferation activity of the tumours. However, in MCL p27 is detected immunohistochemically mainly in blastic variants (Quintanilla-Martinez et al, 1998). The mechanism responsible for this p27 pattern in MCL is not clear but may imply both an increased p27 protein degradation by the proteosome pathway (Chiarle et al, 2000) that in a subset of cases may be related to the accumulation of SKP2 (Lim et al, 2002), and the sequestration of p27 protein by the overexpressed cyclin D1, rendering it inaccessible to antibody detection (Quintanilla-Martinez et al, 2003).

Cyclin D1 may also have an oncogenic potential independently of its CDK cell cycle regulatory function. For example, Cyclin D1 has been shown to regulate a number of transcription factors and transcriptional co-regulators, including STAT3, C/EBPβ, and B-MYB among others, which in some cases appears to occur independent of CDK4-binding activity (Coqueret, 2002). However, it is not known if this transcriptional regulation function is present in MCL cells.

Secondary molecular events contributing to the pathogenesis of MCL

Several experimental observations suggest that cyclin D1 deregulation, although important for MCL initiation, may not be responsible for the complete cell transformation. Transgenic mice that overexpress cyclin D1 did not develop spontaneous lymphomas, and cooperation with other oncogenes like MYC were required for lymphomagenesis (Lovec et al, 1994). Further, a mouse model expressing a constitutively nuclear cyclin D1 in murine lymphocytes developed mature B-cell lymphomas carrying alterations similar to blastoid variants of MCL, including deregulation of the ARF/MDM2/p53 pathway and BCL2 overexpression (Gladden et al, 2006). These results suggest that the development of tumours requires additional oncogenic events, despite the highly lymphomagenic effect of nuclear restricted cyclin D1 expression. In addition, the identification of the t(11;14) translocation in blood cells of 1–2% of healthy individuals without evidence of disease (Hirt et al, 2004) supports the need for additional oncogenic events in the progression of MCL.

Genetic studies have revealed that MCL is one of the malignant lymphoid neoplasms with the highest level of genomic instability (Salaverria et al, 2006) (Table II), with blastoid variants having more complex karyotypes. In addition to frequent chromosomal imbalances, tetraploidy occurs frequently in pleomorphic (80%) and blastic variants (36%) (Ott et al, 1997). Although the pathogenesis of this phenomenon is not well understood, tetraploid cases contain more centrosome anomalies (Kramer et al, 2003) and overexpress centrosome-associated genes (Neben et al, 2007). Preliminary genomic studies of MCL have identified uniparental disomies (UPD) in regions similar to the ones commonly deleted (Nielaender et al, 2006; Rinaldi et al, 2006). These results would support the view of UPD as an alternative mechanism to inactivate tumour suppressor genes (Fitzgibbon et al, 2005).

Table II.   Commonly altered chromosomal regions detected in mantle cell lymphoma by comparative genomic hybridization (Allen et al, 2002; Bea et al, 1999; Bentz et al, 2000) and array-based genomic analysis (Flordal et al, 2007; Karnan et al, 2004; Kohlhammer et al, 2004; Rinaldi et al, 2006; Rubio-Moscardo et al, 2005b; Salaverria et al, 2007; Schraders et al, 2005; Tagawa et al, 2005).
Chromosomal region*Frequency number of cases (%) Suggested target genes†
  1. *Minimal altered regions vary slightly among different studies.

  2. †In bold confirmed target genes.

  3. ‡Homozygous deletions of this gene have been identified in MCL cell lines but not in primary tumours (Tagawa et al, 2005).

3q25-qter32–70ECT2, SERPINI2, ?
7p21-2216–34GPR30, CARD11,ETV1
9q2216–31SYK, GAS1, FANCC
1p13-p3118–52GCLM, CDC14A, DPYD
6q23-q2718–38TNFAIP3, IFNGR1
9p21-p2218–41CDKN2A, ARF1
9q21-qter18–45CDC14B, FANCC, GAS1, c9orf3
10p14-1518–31PRKCQ, KIN, c10orf47
13q14-q3425–70RFP2, ING1, LIG4, TNFSF13B, DLEU1, DLEU2

The identification of the genes targeted by the described chromosome abnormalities has disclosed that most of them are involved in two common pathogenetic pathways, the cell cycle machinery and the cellular response to DNA damage (Fernandez et al, 2005). However, genes implicated in cell survival might also be involved in MCL lymphomagenesis (see below).

Deregulation of cell cycle

Highly proliferative and clinically aggressive MCL carry oncogenic alterations in two major regulatory pathways, INK4a/CDK4/RB1 and ARF/MDM2/p53, which are involved in cell cycle control and senescence (Fig 4). Homozygous deletions of the CDKN2A locus on 9p21 have been detected in 20–30% of blastoid variants but in less than 5% of typical cases (Dreyling et al, 1997; Pinyol et al, 1997). Inactivation of this locus by hypermethylation occurs in other lymphomas but this phenomena seems uncommon and of uncertain significance in MCL (Hutter et al, 2006). This locus encodes for two key regulatory elements, the CDK4 inhibitor INK4a and the p53 regulator ARF. The presence of INK4a deletion may cooperate with cyclin D1 deregulation, promoting G1/S-phase transition in MCL cells by increasing the amount of active cyclin D1/CDK4 complexes. A pathogenetic mechanism alternative to INK4a deletion might be the amplification and overexpression of BMI1, a transcriptional repressor of the CDKN2A locus (Jacobs et al, 1999; Bea et al, 2001). Inactivation of other members of the INK4 family, such as CDKN2B and CDKN2C, occur by homozygous deletion in cell lines and in occasional MCL cases (Williams et al, 1997; Mestre-Escorihuela et al, 2007).


Figure 4.  MCL cells show deregulation of key genes involved in cell cycle control. The t(11;14)(q13;q32) results in the constitutive overexpression of cyclin D1. The cyclin D1 deregulation and occasional amplification and overexpression of CDK4 will promote the hyperphosphorylation and consequent inactivation of RB1. The homozygous deletion of the INK4a/ARF locus that encodes for the CDK inhibitor p16INK4a would ensure the presence of high levels of Cyclin D1/CDK4 activity. As an alternative to the loss of p16INK4a, BMI1 is amplified and/or highly expressed in some MCL cases. The direct inactivation of RB1 also could occur in aggressive MCL variants. The INK4a/ARF locus also encodes for p14ARF that negatively regulates MDM2, which promotes p53 degradation. These alterations and TP53 mutations lead to frequent deregulation of the p53 pathway.

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The identification of CDK4 amplification in some aggressive blastoid MCL strengthens the significance of the G1/S transition deregulation during MCL progression (Hernandez et al, 2005). These gene amplifications occurred almost exclusively in MCL with a wild-type CDKN2A locus, suggesting that CDK4 amplifications are another alternative mechanism of disrupting the RB1-dependent G1/S phase control. Interestingly, early studies of MCL did not identify alterations of this tumour suppressor gene. However, inactivating microdeletions of RB1 have recently been described in some highly proliferative MCL cases (Pinyol et al, 2007). Similarly to the amplification of CDK4, these alterations occurred in cases with a wild-type CDKN2A locus supporting the idea that oncogenic alterations of more than one member of the INK4a/CDK4/RB1 pathway do not seem to provide additional biological advantage for the tumour.

The homozygous deletion of the CDKN2A locus in MCL usually also involves ARF, the main function of which is to stabilize the p53 protein by preventing its MDM2-mediated degradation. The homozygous deletion of this locus determines the simultaneous deregulation of the cell cycle and the p53 pathway. TP53 itself is frequently targeted by genetic alteration in MCL patients. Although TP53 mutations are rarely observed in classical low proliferative MCL they are identified in approximately 30% of highly proliferative blastoid MCL, usually associated with 17p deletion (Greiner et al, 1996; Hernandez et al, 1996). An alternative mechanism to p53 inactivation may be the overexpression of MDM2 that it is detected in a small subset of MCL cases (Hartmann et al, 2007). However, the mechanism driving this MDM2 upregulation is not known. Although, inactivation of TP53 occurs in tumours with wild-type CDKN2A locus, it is associated with CDK4 amplification or RB1 deletions suggesting that the tumours cells may obtain a selective advantage inactivating both ARF/MDM2/p53 and INK4a/CDK4/RB1 pathways. The simultaneous inactivation of these pathways may occur by homozygous deletion of the CDKN2A locus, BMI1 amplification, or by TP53 mutation with concomitant CDK4 amplification or RB1 deletion (Hernandez et al, 2005; Pinyol et al, 2007).

DNA damage response pathway dysfunction

The identification of a high number of chromosome aberrations suggest that alterations of the mechanisms involved in genome stability, such as DNA damage response pathways, may be important for MCL pathogenesis. In this sense, the ataxia-telangiectasia mutated gene (ATM) that plays an essential role in the cellular response to DNA damage is located in 11q22-23, a frequently deleted locus in MCL (Stilgenbauer et al, 1999). ATM mutations have been described in 40–75% of MCL usually associated with the deletion of the wild type allele (Camacho et al, 2002; Fang et al, 2003). ATM is required for the activation of p53 in response to DNA damage and participates during normal immunoglobulin V-D-J recombination in B cells promoting the repair of double strand break lesions (DSBs) (Perkins et al, 2002). A deficient response to DSBs in lymphoid cells might produce genomic instability facilitating the development of lymphomagenic alterations (Kuppers & Dalla-Favera, 2001). In fact, ATM inactivation in MCL is associated with a high number of chromosomal alterations suggesting that its deregulation is important for the accumulation of chromosomal aberrations (Camacho et al, 2002). ATM alterations occur in classical and blastoid MCL variants independently of the proliferation activity and do not appear to be associated with any clinical behaviour or prognosis of the patients, suggesting that ATM inactivation may occur early during MCL lymphomagenesis. The finding of heterozygous germline ATM mutations in MCL patients in which tumour cells subsequently lost the wild-type allele would support the idea that these alterations might represent a predisposing event in these neoplasms. Downstream ATM targets, such as CHEK2 and CHEK1, are also occasionally deregulated in MCL. Decreased protein levels and mutations of CHEK2 have been described in a subset of MCL with a high number of chromosomal imbalances. Similarly to what happen with ATM, CHEK2 mutations have been observed in the germline of some MCL patients suggesting that these mutations might predispose to the development of the tumours (Hangaishi et al, 2002; Tort et al, 2002). CHEK1 protein is downregulated in occasional cases of MCL, but no mutations of the gene have been detected (Tort et al, 2005).

The identification of an altered expression of DNA replication licensing factors in MCL with high number of chromosome abnormalities and checkpoint defects suggest that the failure to appropriately regulate DNA replication could facilitate the accumulation of chromosome aberrations in MCL with a compromised DNA damage response (Pinyol et al, 2006).

Cell survival pathways in MCL

Additional molecular events that mainly deregulate survival and apoptosis mechanisms seem to contribute to the MCL oncogenesis (Fig 5). In particular, amplification of the anti-apoptotic BCL2 and homozygous deletions of BCL2L11, a member of the BH-3 only family with pro-apoptotic activity, have been described in several MCL cell lines, but the importance of these alterations in primary MCL is not clear (Tagawa et al, 2005). Overexpression of MCL1, an antiapoptotic protein of the BCL2 gene family, has been associated with blastoid variants (Khoury et al, 2003). Deletions of 8p21·3, targeting two members of the tumour necrosis factor receptor superfamily (DR4 and DR5), also have been reported in a subset of MCL (Rubio-Moscardo et al, 2005a), but they do not seem to correlate with protein downregulation (Roue et al, 2007). The expression of two tumour necrosis family receptors, CD40 and FAS, which may transduce survival or death signals respectively in B cells, are deregulated in some MCL patients (Clodi et al, 1998; Rummel et al, 2004). Moreover, constitutive activation of the nuclear factor-κB (NFκB), which regulates expression of various genes involved in both survival and apoptotic signalling pathways, has been detected in MCL cell lines and primary tumours with overexpression of downstream targets, such as FADD-like apoptosis regulator or B-lymphocyte stimulator (Martinez et al, 2003; Pham et al, 2003; Fu et al, 2006; Roue et al, 2007).


Figure 5.  A simple schematic view of genetic alterations that affect pathways related with cell survival in MCL cells. Genetic alterations, such as amplifications and overexpression of genes, that will promote cell survival are shown in red, while deregulation (such as deletion or downregulation) of genes raising pro-apoptic signals are represented in green. MCL cells show activation of AKT, NFκB, and mTOR pathways resulting in cell cycle progression and resistance to apoptosis. The upregulation of pro-survival signals like BCL2, MCL1, or FLIP, together with the downregulation of pro-apoptotic genes, such as BCL2L11, TNFRSF10A (DR4) and TNFRSF10B (DR5), FAS, and FADD among others will facilitate the survival of MCL tumour cells.

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The activation of the AKT survival pathway in MCL (Rizzatti et al, 2005), particularly in blastoid cases, associated with the loss of PTEN expression (Rudelius et al, 2006), and the activation of the downstream mTOR pathway might also confer to MCL cells higher proliferation and survival capacity (Peponi et al, 2006). The tyrosine kinase SYK involved in the B-cell receptor signalling pathway and activation of AKT and NFκB in B cells is overexpressed in a subset of MCL due to genomic amplification (Rinaldi et al, 2006).

Clinical manifestations

Most MCL patients have disseminated disease, including generalized lymphadenopathies and bone marrow involvement. Bulky disease and B symptoms are less common (Argatoff et al, 1997; Bosch et al, 1998). Extranodal involvement is almost constant, occurring in more than two extranodal sites in 30–50% of the patients. An extranodal presentation without apparent nodal involvement is observed in only 4–15% of cases. Asymptomatic involvement of the gastrointestinal tract with or without macroscopic lesions is very common, but the detection of this microscopic infiltration rarely modifies the clinical management of the patients (Romaguera et al, 2003; Salar et al, 2006). Central nervous system involvement occurs in 10–20% of the patients; it usually appears as a late event and is part of a resistant disease or generalized relapse with ominous significance (Montserrat et al, 1996; Ferrer et al, 2008). Other extranodal sites are also commonly involved (Argatoff et al, 1997).

Peripheral blood involvement at diagnosis varies among studies, depending partly on the disease definition. Conventional examination may detect leukaemic involvement at diagnosis in 20–70% of the patients. Atypical lymphoid cells may be observed in the peripheral blood in the absence of lymphocytosis (Pittaluga et al, 1996) and they may be detected by flow cytometry in virtually all the patients (Ferrer et al, 2007). Leukaemic involvement may also appear during the evolution of the disease and could represent a manifestation of disease progression. A very aggressive leukaemic form mimicking acute leukaemia has been described in a few patients. These cases have blastoid morphology, complex karyotypes, occasionally with 8q24 anomalies, and very rapid evolution with a median survival of only 3 months (Viswanatha et al, 2000).

The clinical behaviour of MCL patients is aggressive with a median overall survival (OS) of around 3–4 years. However, recent studies have identified a subset of patients with an indolent lymphoid proliferation and longer survival (5–12 years) even without the need of any treatment, suggesting that the biological behaviour of MCL may be more heterogeneous that initially thought (Nodit et al, 2003; Orchard et al, 2003). These patients present with a leukaemic form usually with splenomegaly, in absence of lymphadenopathies. The tumour cells tend to show small cell morphology and carry somatic hypermutations of the IGHV genes. Unfortunately, although these characteristics are commonly seen in patients with indolent evolution, similar manifestations may occur in patients with a more aggressive clinical behaviour, compromising its diagnostic usefulness. Further studies should characterize better this group of patients to more precisely adjust their clinical management to the biology of the tumour.

Prognostic parameters

The different therapeutic approaches do not consider the high heterogeneity in the evolution of the disease in MCL patients. The increasing number of therapeutic options is opening new perspectives for patients but the evaluation of these approaches will require a correct stratification of the patients according to the specific biological risk of their disease. Some of the main clinical parameters associated with poor prognosis are summarized in Table III. Recently, a specific MCL prognostic index (MIPI, Mantle-cell lymphoma International Prognostic Index) based on four independent prognostic factors [age, Eastern Cooperative Oncology Group (ECOG) performance score, lactate dehydrogenase (LDH) and leucocyte count] has shown the capacity to clearly separate MCL patients into three groups with significantly different prognoses (Hoster et al, 2008).

Table III.   Summary of prognostic factors in MCL.
Clinical features
  1. ECOG PS, Eastern cooperative Oncology group Performance Score; WBC, white blood cell; IPI, International Prognostic Index; MIPI, Mantle-cell lymphoma International Prognostic Index.

  2. *Resulted significant in a multivariate analysis with other prognostic factors with respect to overall survival.

(Oinonen et al, 1998; Samaha et al, 1998; Andersen et al, 2002; Tiemann et al, 2005)
(Bosch et al, 1998; Oinonen et al, 1998; Weisenburger et al, 2000; Tiemann et al, 2005)
(Argatoff et al, 1997; Bosch et al, 1998; Oinonen et al, 1998; Samaha et al, 1998; Weisenburger et al, 2000; Andersen et al, 2002; Tiemann et al, 2005)
Lactate Dehydrogensase*
(Bosch et al, 1998; Oinonen et al, 1998; Samaha et al, 1998; Andersen et al, 2002; Tiemann et al, 2005)
WBC count*
(Bosch et al, 1998; Oinonen et al, 1998; Andersen et al, 2002)
(Bosch et al, 1998; Oinonen et al, 1998; Andersen et al, 2002)
(Hoster et al, 2008)
Histological Features
Growth pattern
(Norton et al, 1995; Majlis et al, 1997; Weisenburger et al, 2000; Tiemann et al, 2005)
Cytologic variants
(Argatoff et al, 1997; Bosch et al, 1998; Weisenburger et al, 2000)
Molecular features
Mitotic index
(Argatoff et al, 1997; Bosch et al, 1998; Tiemann et al, 2005)
Ki-67 immunostaining*
(Tiemann et al, 2005)
Microarray Proliferation Signature*
(Rosenwald et al, 2003)
(Schrader et al, 2005)
Topoisomerase II α*
(Schrader et al, 2004)
(Hartmann et al, 2007)
(Nagy et al, 2003)
MYC, MDM2 and CCND1 expression*
(Kienle et al, 2007)
Complex karyotypes, including gains of 3q*, 12q, Xq and losses of 9p, 9q* and 17p
(Bea et al, 1999; Allen et al, 2002; Rubio-Moscardo et al, 2005b; Flordal et al, 2007; Salaverria et al, 2007)
Alterations of TP53
(Hernandez et al, 1996)
Alterations of CCND2A locus
(Pinyol et al, 2000)
Concomitant inactivation of p16/CDK4 and ARF/p53*
(Hernandez et al, 2005)

Early histopathological studies recognized the proliferation of the tumour, evaluated either as the mitotic index or cells expressing the proliferation-associated antigen Ki67, as the best predictor of survival in MCL patients (Argatoff et al, 1997; Tiemann et al, 2005). A tight correlation between Ki67 levels and survival is observed, suggesting that this marker may be useful in the stratification of patients for clinical trials (Katzenberger et al, 2006). New proliferation markers recognized by immunohistochemistry, such as topoisomerase II-alpha or MCM6, may be useful in routinely processed samples and may improve the predictive value of the Ki-67 detection (Schrader et al, 2004, 2005). However, these methods may be hampered by the difficulties in the standardization of the techniques and the reproducibility of the evaluation among observers (De Jong et al, 2007).

The analysis of gene expression profiling in MCL has identified a proliferation signature based on the expression of 20 genes able to clearly discriminate patients with different median survival, confirming that increased proliferation was the best predictor of poor survival (Rosenwald et al, 2003). Previous studies had identified other morphological, genetic, and molecular parameters with prognostic value in MCL patients. Thus, the blastoid cytological variants are associated with shorter survival. Tumours with complex karyotypes and specific chromosomal alterations, such as gains in 3q, 12q, Xq and losses in 9p, 9q, and 17p have a more aggressive clinical evolution (Table III). Molecular investigations have identified the inactivation of p53, CDKN2A locus, and the presence of high levels of cyclin D1 or MDM2 as predictors of shortened survival (Table III). The prognostic impact of most of these parameters merely reflect the proliferation of the tumours; they lose their predictive value in multivariate analysis, suggesting that the proliferation activity may represent an integrator of different oncogenic events (Rosenwald et al, 2003).

Interestingly, some molecular and genetic alterations maintain their prognostic prediction independently of the proliferation of the tumours, suggesting that other factors may also influence the behaviour of the lymphoma or the response to the current treatments. Thus, the quantitative gene expression of MYC, MDM2 and CCND1 seem to have prognostic value independently of the tumour proliferation (Kienle et al, 2007). Similarly, the concomitant inactivation of the two regulatory pathways INK4a/CDK4 and ARF/p53 in MCL was associated with a poor survival that was independent of Ki-67 proliferation index (Hernandez et al, 2005). Interestingly, the impact of the chromosome 3q gains and 9q losses on survival is independent of the microarray proliferation signature, suggesting that a predictive model combining the quantification of the proliferation activity and the genetic profile may improve the estimation of the risk of the patients (Salaverria et al, 2007). These robust molecular and genetic prognostic predictors may become an essential tool in the clinical practice to tailor the best therapy for each patient.

Therapeutic options

For years the standard treatment for patients with MCL has been polychemotherapy, usually based on adriamycin-containing regimens. CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) was the most popular regimen, with complete remission (CR) rates of 20–50% and a median overall survival (OS) of around 3 years. The intensive leukaemic regimen hyper-CVAD (a dose intense, hyperfractionated cyclophosphamide in a CHOP-like combination plus high-dose methotrexate and cytarabine) improved the results of CHOP in non-randomized studies. Fludarabine-containing regimens and other polychemotherapy combinations were also used with no substantial modifications on the outcome of the patients. More recently, the strategies for the management of MCL patients have changed due to the introduction of immunotherapy and new drugs that are more targeted to molecular mechanisms of the disease (Brody & Advani, 2006; Jares et al, 2007). The combination of chemotherapy regimens such as CHOP, hyperCVAD, or FCM (fludarabine, cyclophosphamide, mitoxantrone) with rituximab, a chimeric monoclonal anti-CD20 antibody with limited efficacy as a single agent, can produce impressive overall response rates of up to 80–95% and CR rates of up to 30–87% in previously untreated patients (Forstpointner et al, 2004; Lenz et al, 2005; Romaguera et al, 2005). Although the benefit in terms of OS seems more limited, a recent meta-analysis of randomized controlled trials supports the view that the combination of rituximab with chemotherapy might improve OS in MCL patients (Schulz et al, 2007). The immunotherapy with rituximab as maintenance therapy agent prolongs the response duration after combined rituximab-chemotherapy treatment (Forstpointner et al, 2006). When high-dose chemotherapy regimens or rituximab treatment are combined with autologous stem cell transplantation (autoSCT), preferentially in young patients, early in the course of the disease, and at first remission, high overall and complete response rates are reported, and a significant progression-free survival benefit compared with interferon maintenance have been reported in a randomized clinical trial (Gianni et al, 2003; Dreyling et al, 2005). However, relapse is the main concern, since there is not a plateau in the disease-free survival curves of these patients. Moreover, the impact on OS remains unclear, and longer patient follow-up is required in order to clarify the benefit of these therapeutic approaches. The use of high-dose therapy and allogenic stem cell transplantation (alloSCT), that would have much higher eradicative capacity, is unsuitable for most MCL patients due to the need of good patient performance and the high treatment related mortality. To overcome this high toxicity, nonmyeloablative alloSCT regimens have been developed and could represent an option in patients with relapse mantle-cell lymphoma (Khouri et al, 2003). Recent reports in refractory/relapsed MCL patients showed high responses rates, with progression-free survival of 30–60%, OS 45–65% and related mortality below 30% (Maris et al, 2004; Corradini et al, 2007).

Nonetheless, despite the high rate of response achieved by these multimodal approaches, the majority of patients relapse, meaning that MCL patients are not cured by conventional therapy strategies. The need of novel therapeutic approaches and the increasing understanding of the MCL cell biology have led to the development of new therapeutic agents with antitumour activity that target crucial biological pathways, including cell cycle inhibitors (Flavopiridol, R-roscovitine, UCN-01 and styril sulfones), proteosome inhibitors (Bortezomib), mTOR inhibitors (Sirolimus, Temsirolimus, Everolimus) and histone deacetylase inhibitors (SAHA) among others. These new therapeutic approaches are being investigated in preclinical and preliminary clinical trials with promising results in patients previously treated with aggressive regimens (Kouroukis et al, 2003; Goy et al, 2005; O’connor et al, 2005). The combination of these new strategies with other therapeutic agents, including standard chemotherapy drugs (Haritunians et al, 2007; Weigert et al, 2007), and the correct stratification of the patients according to the specific biological risk of each case may change the management and outcome of MCL patients.


  1. Top of page
  2. Summary
  3. Conclusion
  4. Acknowledgements
  5. References

The MCL represents a paradigm in cancer in which the combined alterations in cell cycle regulatory mechanisms, DNA damage response pathways, and probably some cell survival signals play an important role in its development and progression. The basic mechanism generating the important chromosomal instability of these tumours and the potential target genes of most of these aberrations are not well known. However, recent advances in the comprehension of the biology of MCL cells are offering new perspectives for the design of innovative molecular therapeutic strategies that may improve the outcome of these patients.


  1. Top of page
  2. Summary
  3. Conclusion
  4. Acknowledgements
  5. References

We gratefully acknowledge to all the members of the group for the critical feedback and thoughtful discussions. We specially acknowledge A. López-Guillermo for critical reading of the manuscript. We acknowledge A. Rosenwald and G. Ott from the University of Würzburg for the continuous collaboration on these projects. We apologize to investigators whose work is not cited owing to space restrictions. Research work at our laboratory discussed in the manuscript has been supported by the Comisión Interministerial de Ciencia y Tecnología (CICYT) SAF 05–5855, The Lymphoma Research Foundation, Redes Temáticas de Investigación Cooperativa de Cáncer (RTICC) from the Instituto de Salud Carlos III, Generalitat de Catalunya (2005SGR0870).


  1. Top of page
  2. Summary
  3. Conclusion
  4. Acknowledgements
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