Mir-21 Is Over Expressed in Aggressive SMZL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 624-624
Author(s):  
Marie Bouteloup ◽  
Aurélie Verney ◽  
Lucile Baseggio ◽  
Evelyne Callet-Bauchu ◽  
Pascale Felman ◽  
...  
Keyword(s):  
B Cell ◽  
Mirna Expression ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Mirna Expression Profile ◽  
Splenic Marginal Zone Lymphoma ◽  
B Cell Differentiation ◽  
Mirna Expression Pattern ◽  
Oncogenic Pathways ◽  
Histological Transformation

Abstract Within the group of indolent B cells lymphomas derived from cells of the marginal zone, the pathogenesis of Splenic Marginal Zone Lymphoma (SMZL) remains incompletely characterized, in contrast to MALT lymphoma. However numerous findings recently contributed to a better description of this lymphoma, including its possible association with hepatitis C and the recurrence of 7q deletion. Furthermore, the peculiar pattern of Ig genes mutations and the biased usage of some segments (IGHV1-2) is suggestive of a T-independent Ag driven proliferation, at least at initial steps. The clinical heterogeneity is also marked with a lack of reproducible prognostic factors able to characterize the cases with a more aggressive course or histological transformation. MicroRNA (miRNA) are small non-coding RNA that have a post transcriptional regulation role by inhibiting translation of mRNA in protein and their abnormal expression was already found to contribute to the oncogenesis of various leukemias and lymphomas. The aim of the study was then to identify a miRNA profile of SMZL and to assess if specific miRNAs were associated with biological or clinical characteristics. MiRNA expression profile of SMZL was obtained by quantitative RT-PCR technology (Taqman microRNA Assays Human Panel, Applied Biosystems) which enabled to analyze 365 miRNAs. Six frozen spleen specimens of SMZL (including 2 cases with histological transformation) and 5 frozen specimens of non tumoral spleen (traumatic) were used to compare miRNA levels of expression (2−□□Ct method). Out of these 365 miRNAs, 95 were found to be reproducibly detectable in those samples and were further analyzed. Three miRNA were uniformly overexpressed in SMZL samples as compared to non tumor samples: miR-155 (mean fold change = 3.1), miR-451 (mean = 2.37), miR-486 (mean = 2.7). Conversly, 4 miRNAs were uniformly underexpressed: miR-127 (mean = 0.32), miR-139 (mean = 0.32), miR-335 (mean = 0.26), miR-411 (mean = 0.25). Interestingly, 1 miRNA, miR-21 was specifically found overexpressed only in the 2 transformed cases of SMZL (mean = 3.49) in comparison with the 4 non transformed cases (mean = 0.94). Those results were confirmed in a larger cohort of SMZL patients using a simplex real time PCR (Taqman microRNA Assays Human, Applied Biosystems) on frozen or paraffin embedded samples with a specific overexpression of miR-21 in 10 transformed cases (mean = 14.4), absent in the 6 non transformed cases (mean = 0.9) (Mann Whitney test: p =.0022). MiR-155 plays a key role in B cell differentiation and was already found overexpressed in other lymphomas subtypes. Little is know about the other miR overexpressed except for MiR- 21. MiR-21 is commonly overexpressed in solid tumors and the level of its expression is correlated in tumor growth and metastatic dissemination. It was also found overexpressed in chronic lymphocytic leukaemia and DLBCL (diffuse large B cell lymphoma). In opposite to DLBCL, our results seem to link miR-21’s overexpression with aggressive forms of SMZL. MiR-21 regulates multiple genes associated with apoptosis, migration and invasiveness. Altogether, these data points towards a specific miRNA expression pattern in SMZL and suggests that miR-21 could regulate important oncogenic pathways in transformed SMZL lymphomas.

Deregulated PAX-5 Transcription From a TranslocatedIgH Promoter in Marginal Zone Lymphoma

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3865-3878 ◽  
Author(s):  
Aline M. Morrison ◽  
Ulrich Jäger ◽  
Andreas Chott ◽  
Michael Schebesta ◽  
Oskar A. Haas ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Chain Gene ◽  
Splenic Marginal Zone Lymphoma ◽  
Derivative Chromosome ◽  
B Cell Differentiation ◽  
Loss Of Function

Abstract The PAX-5 gene codes for the transcription factor BSAP, which is expressed throughout B-cell development. Although loss-of-function mutation in the mouse showed an essential role forPax-5 in early B lymphopoiesis, gain-of-function mutations have implicated the human PAX-5 gene in the control of late B-cell differentiation. PAX-5 (on 9p13) has been involved together with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in the recurring t(9;14)(p13;q32) translocation that is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation. Here we have characterized a complex t(2;9;14)(p12;p13;q32) translocation present in a closely related non-Hodgkin’s lymphoma referred to as splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the two promoters of PAX-5 were replaced on the derivative chromosome 14 by an immunoglobulin switch Sμ promoter that was linked to the structural PAX-5 gene upstream of its translation initiation codon in exon 1B. Expression analyses confirmed thatPAX-5 transcription was upregulated due to efficient initiation at the Sμ promoter in the malignant B lymphocytes of patient MZL-1. For comparison we have analyzed PAX-5 expression in another B-cell lymphoma, KIS-1, indicating that transcription from the distalPAX-5 promoter was increased in this tumor in agreement with the previously characterized translocation of the immunoglobulin Eμ enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the J-chain gene, which is thought to be under negative control by BSAP, was not expressed, whereas transcription of the putative target genep53 was unaffected by PAX-5 overexpression. Together these data indicate that the t(9;14)(p13;q32) translocation contributes to lymphoma formation as a regulatory mutation that leads to increasedPAX-5 expression in late B-cell differentiation due to promoter replacement or enhancer insertion.

Deregulated PAX-5 Transcription From a TranslocatedIgH Promoter in Marginal Zone Lymphoma

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3865-3878 ◽  
Author(s):  
Aline M. Morrison ◽  
Ulrich Jäger ◽  
Andreas Chott ◽  
Michael Schebesta ◽  
Oskar A. Haas ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Chain Gene ◽  
Splenic Marginal Zone Lymphoma ◽  
Derivative Chromosome ◽  
B Cell Differentiation ◽  
Loss Of Function

The PAX-5 gene codes for the transcription factor BSAP, which is expressed throughout B-cell development. Although loss-of-function mutation in the mouse showed an essential role forPax-5 in early B lymphopoiesis, gain-of-function mutations have implicated the human PAX-5 gene in the control of late B-cell differentiation. PAX-5 (on 9p13) has been involved together with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in the recurring t(9;14)(p13;q32) translocation that is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation. Here we have characterized a complex t(2;9;14)(p12;p13;q32) translocation present in a closely related non-Hodgkin’s lymphoma referred to as splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the two promoters of PAX-5 were replaced on the derivative chromosome 14 by an immunoglobulin switch Sμ promoter that was linked to the structural PAX-5 gene upstream of its translation initiation codon in exon 1B. Expression analyses confirmed thatPAX-5 transcription was upregulated due to efficient initiation at the Sμ promoter in the malignant B lymphocytes of patient MZL-1. For comparison we have analyzed PAX-5 expression in another B-cell lymphoma, KIS-1, indicating that transcription from the distalPAX-5 promoter was increased in this tumor in agreement with the previously characterized translocation of the immunoglobulin Eμ enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the J-chain gene, which is thought to be under negative control by BSAP, was not expressed, whereas transcription of the putative target genep53 was unaffected by PAX-5 overexpression. Together these data indicate that the t(9;14)(p13;q32) translocation contributes to lymphoma formation as a regulatory mutation that leads to increasedPAX-5 expression in late B-cell differentiation due to promoter replacement or enhancer insertion.

scholarly journals Lymphomas in Patients With Sjögren's Syndrome Are Marginal Zone B-Cell Neoplasms, Arise in Diverse Extranodal and Nodal Sites, and Are Not Associated With Viruses

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 766-775 ◽  
Author(s):  
Bruno Royer ◽  
Dominique Cazals-Hatem ◽  
Jean Sibilia ◽  
Felix Agbalika ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
P53 Protein ◽  
B Cell Lymphoma ◽  
Lymphoid Tissues ◽  
Low Grade ◽  
Human Herpes Virus 8 ◽  
Barr Virus ◽  
P53 Antibodies ◽  
Histological Transformation

Abstract The occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjögren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14; 18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.

Splenic Marginal Zone Lymphoma Shows a Distinct Pattern of DNA Copy Number Aberrations That Correlates with Tumor Characteristics and Predicts Disease Outcome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2422-2422
Author(s):  
Jose A. Martinez-Climent ◽  
Cristina Robledo ◽  
Manuela Mollejo ◽  
Anton Parker ◽  
Juan L. Garcia ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Marginal Zone ◽  
Array Cgh ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Genomic Aberrations ◽  
7Q Deletion

Abstract Splenic marginal zone lymphoma (SMZL) is an indolent B cell malignancy whose diagnosis is based on lymphocyte morphology, immunophenotype and marrow and/or splenic histology. Unlike other lymphomas, there is not a common chromosomal translocation specific for SMZL, and genetic prognostic factors are poorly defined. To investigate the pattern of genomic aberrations in SMZL, we applied comparative genomic hybridization to BAC microarrays (array CGH) to a well characterized series of 75 SMZL specimens. We applied two different 1 Mb-resolution BAC arrays: UCSF HumArray 3.2 and a novel array CGH platform developed at Univ. of Salamanca. These arrays allowed us to detect DNA copy number changes across the genome with high accuracy in 67 of 75 patient samples. Data were compared with our previous array CGH studies of 170 samples from different B-cell lymphoma subgroups. FISH studies for IGH, IGK and IGL translocations and 7q deletion were performed on tissue microarrays in 24 cases. Of the 67 samples, 19 (28%) showed a normal genomic profile. The median number of genomic aberrations per tumor was 2.2 (1.3 gains and 0.9 losses), which was lower than the rates detected in other lymphoma subgroups (diffuse large cell lymphoma, 6.4; mantle cell lymphoma, 6; follicular lymphoma, 4.5) and comparable to MALT lymphomas (2 abnormalities per tumor). SMZL cells showed a genomic pattern characterized by gain of chromosomes 3q24-q29 (18%), 6p (9%), 12q (9%), and 18q (4%) and loss of 7q32 (34%), 8p21-p23 (13%), 17p13 (10%) at P53 locus and 6q21-q27 (9%). Notably, no alterations of the P16/ARF (9p21) or MYC loci (8q24) were detected. Correlation of array CGH data with conventional cytogenetics, FISH and LOH studies revealed a high concordance. Detailed mapping of 7q deletions delineated a consensus region of loss of 3 Mb in 7q32. This 7q deletion was almost exclusive to SMZL, being observed in only 5 of 170 non-SMZL B-cell lymphomas (p=0.0000001). Four cases presented IG-translocation. Mutation of IGH was observed in 62% and correlated with a complex karyotype (61 vs. 13%; p=0,0008) whereas unmutated IGH correlated with the deletion of 7q (56 vs. 23%; p=0,01). Among the various genomic abnormalities, only the deletion of 8p or the presence of a complex karyotype correlated with inferior overall survival (OS) (median OS, 58 vs. 110 months, p=0,004; and 60 vs. 105 months, p=0,01; respectively). In summary, array CGH has defined a pattern of genomic aberrations in SMZL that differs from other B-cell lymphoma subgroups and that may predict overall survival. Because the deletion of 7q32 is the most distinctive genetic marker in SMZL, the identification of a putative tumor suppressor gene inactivated within the region of deletion seems mandatory.

The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 627-632 ◽  
Author(s):  
Dan Jones ◽  
Richard J. Benjamin ◽  
Aliakbar Shahsafaei ◽  
David M. Dorfman
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chemokine Receptor ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Lymphocytic Leukemia ◽  
Splenic Marginal Zone Lymphoma ◽  
Flow Cytometric

Chemotaxis in leukocytes is mediated through binding of soluble chemokines to transmembrane G-protein coupled receptors. The chemokine receptor CXCR3 has been previously shown to be widely expressed on activated T cells and to mediate T-cell chemotaxis on binding to various ligands, including Mig, IP-10, and ITAC. By using immunohistochemical and flow cytometric analysis, we report that CXCR3 is also expressed on a subset of peripheral blood B cells and in distinct subtypes of B-cell lymphoma. CXCR3 immunohistochemical or flow cytometric expression was seen in 37 of 39 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (diffusely positive in 33 cases), whereas mantle cell lymphoma (30 cases), follicular lymphoma (27 cases), and small noncleaved cell lymphoma (8 cases) were negative in all but 2 cases. Strong CXCR3 expression was also seen in splenic marginal zone lymphoma (14 of 14 cases) and in the monocytoid and plasmacytic cells in extranodal marginal zone lymphoma (15 of 16 cases). This differential expression of CXCR3 in B-cell tumors contrasts with that of another B-cell–associated chemokine receptor, BLR1/CXCR5, which we show here is expressed on all types of B-cell lymphoma tested. We also report that the CXCR3 ligand, Mig, is coexpressed on tumor cells in many cases of CLL/SLL (10 of 13 cases examined) with Mig expression less frequently seen in other B-cell lymphoma subtypes. Coexpression of CXCR3 and its ligand, Mig, may be an important functional interaction in B-CLL, as well as a useful diagnostic marker for the differential diagnosis of small cell lymphomas.

miRNA expression profiling of CD20+ plasma cell myeloma (PCM): Upregulation of miR-155 shedding new insight into disease biology and clinicopathologic behavior.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8108-8108
Author(s):  
Ravindra Kolhe ◽  
Anand P. Jillella ◽  
Kavita Natrajan ◽  
Farrukh Tauseef Awan ◽  
Elizabeth Manaloor ◽  
...  
Keyword(s):  
B Cell ◽  
Plasma Cell ◽  
Mirna Expression ◽  
Cell Activation ◽  
Expression Profiles ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Sh2 Domain ◽  
Clinicopathological Parameters ◽  
B Cell Differentiation

8108 Background: Up to15-20% of patients with PCM have expression of CD20, although the significance of this remains unclear. The prognostic significance of CD20 expression in PCM is unclear. Recently, a class of noncoding RNAs, miRNAs, were identified as critical gene regulators in cell growth, disease, and development. Our study investigates importance of miRNAs in cases of CD20+ PCM and correlates them with clinicopathological parameters. Methods: The miRNA expression profile of CD20+ PCM (n=6), diffuse large B cell lymphoma (DLBCL) (n=6), and CD20 negative PCM (n=8) were evaluated using the Affeymertrix miRNA microarray platform on GeneChip miRNA 2.0 array in paraffin-embedded samples. After hybridization and data acquisition, we used Partek Genomics Suite software for RMA normalization and to determine statistically significant differences in miRNA expression between experimental groups by ANOVA and pairwise comparisons (two-sided α=0.05). Results: miRNA expression profiles of CD20+ PCM, show upto >4 times upregulation of 7 miRNAs and downregulation of 8 miRNAs. miR-155, the miRNA upregulated in various B cell lymphomas and plays a key role in the lymphomagenesis, was amongst the highest miRNAs that were upregulated. Conclusions: miR-155 is known to repress SH2-domain containing inositol-5-phosphatase-1 (SHIP-1), which is a critical phosphatase that negatively down modulates AKT pathway and has functions during normal B-cell development. Physiologically, miR-155 is upregulated during B-cell activation upon antigen stimulation and so plays a role in antibody class switching and plasma cell formation. We propose that this overexpression of miR-155 in CD20+ PCM unblocks AKT activity, inducing cell proliferation and may explain some of the immunophenotypic behavior of CD20+ PCM. This work is intriguing for the new information it provides about the role of miR-155 in CD20+ PCM. Furthermore, the phenotype of miR-155+ve CD20+ PCM might ultimately provide new insights into regulation of poorly understood steps in B cell differentiation and maturation into plasma cell and more importantly the clinicopathological behavior of this entity.

Gene Expression Profiling of Post-Follicular B-Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 617-617
Author(s):  
Wee-Joo Chng ◽  
Gaofeng Huang ◽  
Paul J. Kurtin ◽  
Ahmet Dogan ◽  
Ellen Remstein
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Splenic Marginal Zone Lymphoma ◽  
Major Cluster ◽  
Significant Enrichment

Abstract Although classified as marginal zone lymphomas under the WHO classification, the molecular relationship between splenic marginal zone lymphoma (SMZL), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), and nodal marginal zone lymphoma (NMZL) has not been clarified. Furthermore, lymphoplasmacytic lymphoma (LPL) can show clinical morphologic and immunophenotypic overlap with these entities and may present a diagnostic challenge. In this analysis of gene expression data generated using the Affymetrix U133plus 2.0 chip from 32 SMZL, 25 MALTs (GI, salivary gland and lung), 23 NMZL and 25 LPL, we aim to identify the molecular relationship between these pathological entities using unsupervised methods, identify disease specific signatures and markers using supervised methods and also the functional implications of these signatures using a modified gene-set enrichment analysis. Using hierarchical clustering, MALT lymphoma forms a tight cluster regardless of tumor site. In addition, SMZL and NMZL form another large cluster. LPLs are divided into 2 main clusters with occasional samples interspersed amongst the SMZL and NMZL. There is no correlation between the percentage of CD20-positive B-cells, CD3-positive T-cells or CD138- positive plasma cells or tissue origin of the tumor and the way the samples are clustered. However, the separation of the LPLs into 2 major cluster correspond to the presence and absence of underlying Waldenstrom Macroglobulinaemia (WM), suggesting that the genes distinguishing the 2 clusters are potential markers for differentiating WM LPL from non-WM LPL. Next, using supervised analysis we identified a cluster of genes including MMP7, LTF and SFRP2 with high signals specific to MALTs, while other genes including PRDM1 (BLIMP1), XBP1 and TNFRSF17 (BCMA) were specifically over-expressed in LPL. These may therefore represent novel diagnostic marker differentiating these entities. Several of these are further validated at the protein level using immunohistochemistry on a tissue microarray. Consistent with the unsupervised analysis, SMZL and NMZL have little difference and share the over-expression of CD22 and WNT3 among other genes. Clustering of these samples based on the pathways and genesets that are enriched in the individual tumors as compared to their normal tissue counterpart showed a mutually exclusive pattern with significant enrichment of NFKB-related genesets and genes in LPL and MALT, and significant enrichment of B-cell receptor signaling genesets and genes in SMZL and NMZL. Our analysis, for the first time, describes the molecular relationship between these closely related lymphomas. In the process, we identified novel diagnostic markers that may differentiate these conditions and also new insights into molecular pathways that are differentially activated in the different conditions. These may represent potential therapeutic targets

Monoclonal B-Cell Lymphocytosis Exhibiting Immunophenotypic Features Consistent with Marginal Zone Origin: What Is This Entity?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1587-1587
Author(s):  
Aliki Xochelli ◽  
Panagiotis Baliakas ◽  
Anne Gardiner ◽  
Sarah Mould ◽  
Zadie Davis ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Conflicts Of Interest ◽  
Single Case ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Gastric Malt Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Group A ◽  
Immunogenetic Analysis

Abstract Abstract 1587 Monoclonal B-cell lymphocytosis (MBL) with an immunophenotype consistent with marginal zone origin (MBL-MZ), that can be either CD5− or CD5+ but atypical for CLL, and also lacking an IGH/CCND1 translocation, is an increasingly recognised entity with poorly understood biological background and clinical significance. In particular, it is not yet clarified whether it represents a precursor state to one of the distinct lymphoma entities recognized by WHO as deriving from MZ cells or whether it constitutes a novel entity, likely with similar ontogeny. To obtain insight into this issue we retrospectively evaluated a series of 71 patients (male/female: 35/36, median age: 73.3 years) with lymphocytosis (median lymphocyte count: 5.77 × 109/l) detected incidentally on a routine blood test. No case had lymphadenopathy, organomegaly or any clinical features to suggest a concurrent marginal zone lymphoma. Hemoglobin and platelet counts were normal in all cases; 15/57 (26%) cases had paraproteinemia. Peripheral blood immunophenotyping revealed the presence of a clonal B-cell population with Matutes score <2 in all cases. Individual markers were expressed as follows: CD5: 15/71, CD23: 7/70, CD79β: 60/64, FMC7: 50/67, CD49d: 35/35, CD38: 6/53. In 8/45 cases assessed with CT-scan and/or ultrasound, borderline splenomegaly was observed. Histopathological examination of the bone marrow biopsy (BMB) was available in 11 cases and demonstrated mostly mixed patterns of neoplastic lymphocytic inflitration from small B cells. Karyotype data were available in 66 cases; 48/66 (72.7%) had abnormal karyotype. Main cytogenetic findings are as follows: (1) translocations: n=16 cases of which 3 carried t(2;7)(p11;q21/22); (2) isochromosome 17q: n=8; (3) trisomy 12: n=8; (4) del(7q): n=7; (5) trisomy 3: n=4. Immunogenetic analysis revealed overusage of the IGHV4–34 gene (15/63, 23.8%). Notably, the IGHV1–2 gene was utilized by a single case, thus sharply contrasting (p<0.0001) splenic marginal-zone lymphoma (SMZL) with a reported frequency of IGHV1–2 in excess of 30%. Seven of 63 rearrangements (11.1%) carried IGHV genes with no somatic mutations, whereas the remainder (56/63, 88.9%) exhibited some impact of somatic hypermutation (SHM), ranging from minimal to (mostly) pronounced. Overall, cases of the present study exhibited a significantly (p<0.005) higher SHM load compared to SMZL. With a median follow-up of 4.9 years (0.8–20), 54 cases (group A) remain stable with no signs of progression. The remaining 17 cases (group B) have MBL along with clinical or histopathologic evidence of lymphoma. In particular: (i) a female with MBL as an incidental finding, also carrying t(2;7), was eventually diagnosed with gastric MALT lymphoma at +11 months from presentation; immunogenetic analysis confirmed clonal identity between the MBL and the lymphoma; (ii) 2 cases developed lymphadenopathy; (iii) a single case developed diffuse large B cell lymphoma of the skin; and, (iv) 13 cases developed splenomegaly and, thus, can be considered as either SMZL or splenic lymphoma/leukemia unclassifiable (SLLU). Groups A and B did not differ in terms of demographics, diagnostic blood counts (including clonal MBL count) and SHM status; the only difference concerned cytogenetic profiles, with i(17)(q10) and del(7q) being almost exclusive to group A. In conclusion, we demonstrate that MBL-MZ can be the presenting feature of occult MZ lymphoma, most frequently SMZL/SLLU. However, in a sizeable proportion of cases, MBL-MZ remains stable over time with no evidence of organ involvement and distinct immunogenetic features from SMZL, thereby raising the possibility that it might represent a newcomer to the spectrum of B-cell lymphoproliferations of MZ origin. Disclosures: No relevant conflicts of interest to declare.

Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 4930-4934 ◽  
Author(s):  
Davide Rossi ◽  
Silvia Deaglio ◽  
David Dominguez-Sola ◽  
Silvia Rasi ◽  
Tiziana Vaisitti ◽  
...  
Keyword(s):  
B Cell ◽  
Somatic Mutations ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Common Mechanism ◽  
Splenic Marginal Zone Lymphoma ◽  
Therapeutic Approaches ◽  
Molecular Alterations ◽  
Suitable Target

Abstract Splenic marginal zone lymphoma (SMZL) is one of the few B-cell lymphoma types that remain orphan of molecular lesions in cancer-related genes. Detection of active NF-κB signaling in 14 (58%) of 24 SMZLs prompted the investigation of NF-κB molecular alterations in 101 SMZLs. Mutations and copy number abnormalities of NF-κB genes occurred in 36 (36%) of 101 SMZLs and targeted both canonical (TNFAIP3 and IKBKB) and noncanonical (BIRC3, TRAF3, MAP3K14) NF-κB pathways. Most alterations were mutually exclusive, documenting the existence of multiple independent mechanisms affecting NF-κB in SMZL. BIRC3 inactivation in SMZL recurred because of somatic mutations that disrupted the same RING domain that in extranodal marginal zone lymphoma is removed by the t(11;18) translocation, which points to BIRC3 disruption as a common mechanism across marginal zone B-cell lymphomagenesis. Genetic lesions of NF-κB provide a molecular basis for the pathogenesis of more than 30% of SMZLs and offer a suitable target for NF-κB therapeutic approaches in this lymphoma.

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