A case of mantle cell lymphoma with meningioma

Mantle cell lymphoma (MCL) is an uncommon type of gastrointestinal lymphoma. MCL is a distinct subtype of B-cell non-Hodgkin lymphomas. The major subtype of MCL is characterized by the presence of multiple lymphomatous polyposis (MLP), in which multiple polyps are observed along the gastrointestinal tract. The malignant cells express pan B-cell marker and the T-cell marker cluster of differentiation 5. The chromosomal translocation t(11;14)(q13;q32) that causes cyclin D1 overexpression is commonly observed on the cytogenetic analysis of MCL. Survival improvement has recently been achieved for patient with MCL by the successful introduction of monoclonal antibodies and dose-intensified approaches for treatment, including autologous stem cell transplantation strategies. Some reports suggest that there is an increased incidence of second malignancies in patients with MCL or lymphoma. We report a case of MCL involving the colon; the patient was a 60-year-old man who complained of low abdominal discomfort during defecation. During the workup, a meningioma was unexpectedly discovered. On analysis, the tumor was found to be a t(11;14)-negative and non-MLP-type MCL.     

MicroRNA-650 expression is influenced by immunoglobulin gene rearrangement and affects the biology of chronic lymphocytic leukemia

MicroRNAs (miRNAs) play a key role in chronic lymphocytic leukemia as well as in normal B cells. Notably, miRNA gene encoding miR-650 and its homologs overlap with several variable (V) subgenes coding for lambda immunoglobulin (IgLλ). Recent studies describe the role of miR-650 in solid tumors, but its role in chronic lymphocytic leukemia (CLL) has not yet been studied. Our experiments demonstrate that miR-650 expression is regulated by coupled expression with its host gene for IgLλ. This coupling provides a unique yet unobserved mechanism for microRNA gene regulation. We determine that higher expression of miR-650 is associated with a favorable CLL prognosis and influences the proliferation capacity of B cells. We also establish that in B cells, miR-650 targets proteins important in cell proliferation and survival: cyclin dependent kinase 1 (CDK1), inhibitor of growth 4 (ING4), and early B-cell factor 3 (EBF3). This study underscores the importance of miR-650 in CLL biology and normal B-cell physiology.     

Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL)

Cutaneous T-cell lymphomas (CTCLs) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult because of a clinical and histologic resemblance to benign inflammatory skin diseases. To address whether microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we studied miRNA expression levels in 198 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays, we show that the most induced (miR-326, miR-663b, and miR-711) and repressed (miR-203 and miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Quantitative (q)RT-PCR analysis of 103 patients with CTCL and benign skin disorders validates differential expression of 4 of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A qRT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity and sensitivity, and with a classification accuracy of 95%, indicating that miRNAs have a high diagnostic potential in CTCL.     

Mantle-cell lymphoma.

Mantle-cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive pregerminal center cells characterized by a nodular or diffuse proliferation of atypical lymphoid cells with a monoclonal B-cell phenotype and coexpression of CD5. Two cytologic variants have been identified, typical and blastic. Typical cases show a proliferation of small to intermediately sized lymphoid cells with irregular nuclei and scarce cytoplasm. Blastic variants include a spectrum of intermediate to large cells with round or irregular nuclei and finely dispersed chromatin. These cases have a higher proliferative activity and a more aggressive clinical evolution. MCL is genetically characterized by 11q13 translocations and bcl-1 rearrangement. This alteration leads to a constant overexpression of cyclin D1, which plays an important pathogenetic role, probably deregulating cell-cycle control by overcoming the suppressor effect of retinoblastoma protein (Rb) and p27Kip1. Detection of cyclin D1 may be used as a highly specific marker of MCL because it is expressed in virtually all of these tumors, but in only a few reported cases of aggressive variants of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and a small percentage of cases of multiple myeloma. Aggressive variants have additional genetic alterations, including inactivation of p53 and p16INK4a tumor-suppressor genes. Clinically, MCL presents in elderly males with advanced disease and frequent extranodal involvement, particularly with involvement of bone marrow, gastrointestinal tract, and spleen. The clinical evolution is relatively aggressive, with poor response to conventional therapeutic regimens and a median survival duration of 3 to 4 years. Further studies are needed to define better new therapeutic strategies for the management of these patients.     

The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice

The miR-17-92 cluster and its 6 encoded miRNAs are frequently amplified and aberrantly expressed in various malignancies. This study demonstrates that retroviral-mediated miR-17-92 overexpression promotes expansion of multipotent hematopoietic progenitors in mice. Cell lines derived from these miR-17-92-overexpressing mice are capable of myeloid and lymphoid lineage differentiation, and recapitulate the normal lymphoid phenotype when transplanted to nonobese diabetic/severe combined immunodeficiency mice. However, overexpression of individual miRNAs from this locus, miR-19a or miR-92a, results in B-cell hyperplasia and erythroleukemia, respectively. Coexpression of another member of this cluster miR-17, with miR-92a, abrogates miR-92a-induced erythroleukemogenesis. Accordingly, we identified several novel miR-92a and miR-17 target genes regulating erythroid survival and proliferation, including p53. Expression of this critical target results in marked growth inhibition of miR-92a erythroleukemic cells. In both murine and human leukemias, p53 inactivation contributed to the selective overexpression of oncogenic miR-92a and miR-19a, and down-regulation of tumor-suppressive miR-17. This miR-17-92 expression signature was also detected in p53- B-cell chronic lymphocytic leukemia patients displaying an aggressive clinical phenotype. These results revealed that imbalanced miR-17-92 expression, also mediated by p53, directly transforms the hematopoietic compartment. Thus examination of such miRNA expression signatures should aid in the diagnosis and treatment of cancers displaying miR-17-92 gene amplification.     

Histopathology of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a relatively rare lymphoma, accounting for less than 10% only of all lymphomas. Its morphology is quite homogeneous, but it varies strikingly in about 10% of the cases, making the diagnosis of MCL challenging for histopathologists. The definition of the disease was greatly influenced by the discovery of the translocation t(11;14)(q13,q32), which juxtaposes the cyclin D1 and the immunoglobulin heavy chain genes and is present in the vast majority of MCL cases. The introduction of monoclonal antibodies for the detection of cyclin D1 expression into the diagnostic procedure substantially improved the reproducibility and reliability of the pathological diagnosis. However, new challenges for histopathologists have arisen over the last years, among which are the detection of cyclin D1-negative MCL cases and clinically relevant prognostic subgroups.     

MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n = 49) and CD138+ bone marrow PCs from subjects with MM (n = 16), monoclonal gammopathy of undetermined significance (MGUS) (n = 6), and normal donors (n = 6). We identified overexpression of miR-21, miR-106b approximately 25 cluster, miR-181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17 approximately 92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17 approximately 92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR106b approximately 25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.     

The role of miRNAs in the pathogenesis and diagnosis of B-cell lymphomas

There is a demand to understand B-cell lymphoma pathogenesis better, to identify new markers, and to define multiple lymphoproliferative disorders more accurately. MicroRNAs (miRNAs) are regulators of protein translation, comprising a group of more than 1500 short noncoding single-strand RNA molecules of approximately 22 nucleotides in length. They are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum. Expression of individual miRNAs and miRNA signatures allows specific cell-differentiation stages to be identified, and is a powerful diagnostic and prognostic method. Here we review what is known about the pathogenic relevance of miRNAs, and use of miRNAs for the diagnosis and prognosis of B-cell lymphomas. Most of the published data concern chronic lymphocytic lymphoma and diffuse large B-cell lymphoma, and implicate miRNAs in the pathogenesis of these diseases. They identify miRNAs that could be used for diagnosis, prognosis, or prediction of response to specific therapies.     

Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma

Mantle cell lymphoma (MCL) is a distinct clinicopathologic entity of non-Hodgkin's lymphoma, characterized by a monotonous proliferation of small to medium-sized lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course, and frequent t(11;14)(q13;q32) translocation. We examined 151 cases of lymphoma with MCL morphology from a viewpoint of cyclin D1 overexpression, which is now easily detectable by immunohistochemistry. 128 cases (85%) showed positive nuclear staining for cyclin D1, while the remaining 23 (15%) were negative. Except for cyclin D1 immunohistochemistry, current diagnostic methods, including morphological and phenotypical examinations, could not make this distinction. Although both the cyclin D1-positive and -negative groups were characterized by male predominance, advanced stages of the disease, frequent extranodal involvement, and low CD23 reactivity, the cyclin D1-positive group showed a higher age distribution (P =.04), larger cell size (P =.02), higher mitotic index (P =.01), more frequent gastrointestinal involvement (P =.05), higher international prognostic index score (P =.05), and lower p27(KIP1) expression (P <.0001). Of particular interest is that cyclin D1-positive MCL showed significantly worse survival than cyclin D1-negative lymphoma (5-year survival: 30% versus 86%, P =.0002), which was confirmed by multivariate analysis to be independent of other risk factors. These data suggest that cyclin D1-positive and -negative groups may represent different entities and that the former closely fits the characteristics of classical, typical MCL. We therefore propose that cyclin D1-positivity should be included as one of the standard criteria for MCL, and that innovative therapies for this incurable disease should be explored on the basis of the new criteria.     

Ordered progression of stage-specific miRNA profiles in the mouse B2 B-cell lineage

Micro-RNAs (miRNAs) have been recognized as critical regulators of gene expression, and deregulation of miRNA expression has been implicated in a wide spectrum of diseases. To provide a framework for the role of miRNAs in B-cell development and malignancy, we deep-sequenced miRNAs from B1 cells and 10 developmental stages that can be identified within the mouse B2 B-cell lineage. The expression profiles of the 232 known miRNAs that are expressed during B-cell development display stage-specific induction patterns, yet hierarchical clustering analysis showed relationships that are in full agreement with the model of the B2 B-cell developmental pathway. Analysis of exemplary miRNA expression profiles (miR-150, miR-146a, miR-155, miR-181) confirmed that our data are in agreement with previous results. The high resolution of the expression data allowed for the identification of the sequential expression of oncomir-1/miR-17-92 and its paralogs miR-106a-363 and miR-106b-25 in subsequent developmental stages in the BM. Further, we have identified and validated 45 novel miRNAs and 6 novel miRNA candidates expressed in developing B cells.     

Cyclin Dl expression in B-cell non Hodgkin lymphoma

Disorders of the cell cycle regulatory machinery play a key role in the pathogenesis of cancer. Over-expression of cyclin D1 protein has been reported in several solid tumors and certain lymphoid malignancies, but little is known about the effect of its expression on clinical behavior and outcome in B-cell Non-Hodgkin lymphoma (NHL). In this study, we investigated the expression of cyclin Dl in group of patients with NHL and correlated the results with the clinical and laboratory data. The degree of expression of cyclin Dl protein was evaluated by flow cytometry in a group of NHL patients (n = 46) and in normal control group (n = 10). Cyclin Dl over expression was detected in 10 out of 46 (21.7%) patients; they were 5/5-mantle cell lymphoma (MCL) (100%) and 5/28 large B-cell lymphoma (17.8%). All other NHL subtypes showed normal cyclin D1 expression. The clinical signs (hepatomegaly, splenomegaly and B-symptoms, clinical staging) and laboratory data (hemoglobin, white cell count (WBCs), platelet count, and bone marrow infiltration) were not significantly different between NHL subgroup with cyclin Dl over expression and that with normal cyclin Dl expression. Serum lactic dehydrogenase (LDH) levels and lymphadenopathy were significantly higher in NHL group with cyclin D1 over expression as compared to those without. Also, cyclin D1 over expression is associated with poor outcome of NHL patients. Cyclin Dl over expression was evident among all cases of MCL and few cases of large B-cell lymphoma. Cyclin Dl over expression might be used as adjuvant tool for diagnosis of MCL; has role in NHL biology and is bad prognostic index in NHL.     

Clinical practice guidelines for diagnosis, treatment, and follow-up of patients with mantle cell lymphoma. Recommendations from the GEL/TAMO Spanish Cooperative Group

Mantle cell lymphoma (MCL) is considered a distinct type of B-cell lymphoma genetically characterized by the t(11;14) translocation and cyclin D1 overexpression. There is also a small subset of tumors negative for cyclin D1 expression that are morphologically and immunophenotypically indistinguishable from conventional MCL. Although in the last decades, the median overall survival of patients with MCL has improved significantly, it is still considered as one of the poorest prognoses diseases among B-cell lymphomas. Election of treatment for patients with MCL is complex due to the scarcity of solid evidence. Current available data shows that conventional chemotherapy does not yield satisfactory results as in other types of B-cell lymphomas. However, the role of other approaches such as autologous or allogenic stem cell transplantation, immunotherapy, the administration of consolidation or maintenance schedules, or the use of targeted therapies still lack clear indications. In view of this situation, the Spanish Group of Lymphomas/Autologous Bone Marrow Transplantation has conducted a series of reviews on different aspects of MCL, namely its diagnosis, prognosis, first-line and salvage treatment (both in young and elderly patients), new targeted therapies, and detection of minimal residual disease. On the basis of the available evidence, a series of recommendations have been issued with the intention of providing guidance to clinicians on the diagnosis, treatment, and monitoring of patients with MCL.     

Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.     

Dysregulation of microRNAs and their association in the pathogenesis of T-cell lymphoma/leukemias

MicroRNAs (miRNAs) are non-coding regulatory RNAs consisting of 20–24 nucleotides. Over 4,500 miRNAs have been identified in humans, and it is known that nearly all human protein-encoding genes can be controlled by miRNAs in both healthy and malignant cells. Abnormal miRNA expression is known to occur in many cancers, including in malignant lymphomas (MLs). Detailed genome-wide miRNA expression analysis has been performed in various ML subtypes, and these analyses have led to the discovery of subtype-specific miRNA alterations. Actually, in B-cell lymphomas, several miRNAs have been used as prognostic markers, and their targets are for new agents for ML therapy. Successful studies for delineating miRNA functions in B-cell lymphomas lead us to hypothesize that miRNA dysregulation may also be deeply associated with the pathogenesis of T-cell lymphomas. Indeed, studies for delineating essential miRNAs have been conduced against comparatively well-defined T-cell lymphoma entities. In this review, we describe several key miRNAs and their targets in distinct T-cell lymphoma subsets and their roles in their pathogenesis, studies of which will lead to new therapeutic strategies against T-cell lymphomas.     

Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a clinicopathologic entity that is difficult to diagnose on histopathologic criteria. Approximately 50% to 70% of MCL contain a t(11;14)(q13;q32) translocation involving the cyclin D1 gene. Irrespective of this rearrangement, almost all MCL show overexpression of the cyclin D1 gene at the mRNA level. Other B-cell non-Hodgkin's lymphomas (NHL) do not show this rearrangement or overexpression of cyclin D1. We developed an immunohistochemical assay to detect overexpression of the cyclin D1 protein on conventional formalin-fixed, paraffin-embedded biopsies using the well-defined monoclonal antibody DCS-6. Expression in tumor cells was compared with expression of cyclin D1 in endothelial cells and fibroblasts. An exclusively nuclear staining pattern was observed. Moreover, expression was directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the BCL-1 locus. Of 13 MCL that were analyzed by immunohistochemistry and immunoblot, 12 showed overexpression with both techniques, whereas no overexpression was observed in 39 other NHL. Of 13 additional MCL studied either by immunohistochemistry or immunoblot, 11 also showed overexpression. Two lymphomas morphologically indistinguishable from MCL but with an aberrant immunophenotype (CD5 negative, CD10 positive) both lacked overexpression of cyclin D1. These results underscore the significance of overexpression of the cyclin D1 protein as a specific marker for MCL. Detection of cyclin D1 overexpression on formalin-fixed, paraffin- embedded tissues using the DCS-6 monoclonal antibody can be applied for routine diagnostic purposes.