Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma

The B-cell receptor signaling pathway is important in the lymphomagenesis of many lymphomas, including marginal zone lymphoma (MZL). Herein we describe a case of extranodal MZL refractory to multiple lines of therapy. The presence of an IgM paraprotein prompted further evaluation, and the patient was found to have an MYD88L265P mutation. Treatment with ibrutinib led to a dramatic response with prompt resolution of symptoms and significant improvement in measurable sites of disease. The excellent response to ibrutinib in our patient with MYD88L265P-mutated refractory MZL supports a biological rationale for its use.

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Improved biological insight and influence on management in indolent lymphoma. Talk 3: update on nodal and splenic marginal zone lymphoma

Hematology ◽

10.1182/asheducation-2017.1.371 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 371-378 ◽

Cited By ~ 5

Author(s):

Catherine Thieblemont

Keyword(s):

B Cell ◽

Signaling Pathways ◽

Marginal Zone ◽

Cell Receptor ◽

Nuclear Factor Κb ◽

Therapeutic Strategies ◽

Tumor Burden ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

B Cell Signaling

Abstract Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are rare indolent chronic B-cell lymphomas. Prognosis is typically good with median survival around 10-15 years. Management is generally based on the presence of symptoms or high tumor burden. There are no standard treatments for these 2 entities, and therapeutic strategies are rapidly evolving. Clinical developments for these 2 entities are oriented by genomic studies, with largely overlapping mutational profiles involving the NOTCH, B-cell receptor (BcR) and nuclear factor κB (NF-κB) signaling, chromatin remodeling, and the cytoskeleton. Although new therapeutic options based on targeting signaling pathways and overcoming resistance are increasingly available, few specific prospective studies are performed for these rare subtypes, limiting the conclusions that can be drawn. Novel drugs targeting B-cell signaling have shown promise, including ibrutinib and copanlisib. The second-generation oral immunomodalator (IMiD) lenalidomide showed impressive results when combined with rituximab. Other potential solutions include targeting the NF-κB, JAK/STAT, BCL2, NOTCH, and Toll-like receptor signaling pathways; however, studies in these 2 MZL entities are yet to prove a definitive benefit. Molecular profiling is now a cornerstone of diagnostic, prognostic, and therapeutic strategies to offer patient- and disease-specific solutions. The development of a wider range of effective targeted therapies and prognostic biomarkers is keenly awaited and is expected to strongly affect the natural history of SMZL and NMZL.

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The B cell receptor in marginal zone lymphoma ontogeny and evolution

Annals of Lymphoma ◽

10.21037/aol-20-18 ◽

2020 ◽

Vol 4 ◽

pp. 10-10

Author(s):

Laura Zaragoza-Infante ◽

Andreas Agathangelidis ◽

Maria Papaioannou ◽

Anastasia Chatzidimitriou ◽

Kostas Stamatopoulos

Keyword(s):

B Cell ◽

Marginal Zone ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

B Cell Receptor

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Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis

Blood ◽

10.1182/blood-2004-10-3898 ◽

2005 ◽

Vol 106 (5) ◽

pp. 1831-1838 ◽

Cited By ~ 110

Author(s):

Elena Ruiz-Ballesteros ◽

Manuela Mollejo ◽

Antonia Rodriguez ◽

Francisca I. Camacho ◽

Patrocinio Algara ◽

...

Keyword(s):

B Cell ◽

Cdna Microarray ◽

Marginal Zone ◽

Prognostic Markers ◽

Variable Region ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

Molecular Entity ◽

Splenic Marginal Zone Lymphoma ◽

Mutational Status

Abstract Splenic marginal zone lymphoma (SMZL) is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown. This hampers differential diagnosis with other small B-cell malignancies. With the aim of characterizing this tumor more comprehensively, and of identifying new diagnostic and prognostic markers, we performed cDNA microarray expression profiling and tissue microarray (TMA) immunohistochemical studies in a relatively large series of 44 SMZLs. The results were related to immunoglobulin heavy chain variable region (IgVH) mutational status and clinical outcome. SMZLs display a largely homogenous signature, implying the existence of a single molecular entity. Of the genes deregulated in SMZLs, special mention may be made of the genes involved in B-cell receptor (BCR) signaling, tumor necrosis factor (TNF) signaling and nuclear factor-κB (NF-κB) activation, such as SYK, BTK, BIRC3, TRAF3, and LTB. Other genes observed were SELL and LPXN, which were highly expressed in spleen, and lymphoma oncogenes, such as ARHH and TCL1. In contrast, the genes CAV1, CAV2, and GNG11 located in 7q31, a commonly deleted area, were down-regulated in the entire series. A comparison with the genes comprising the signature of other small B-cell lymphomas identified 3 genes whose expression distinguishes SMZL, namely ILF1, SENATAXIN, and CD40. Shorter survival was associated with CD38 expression, naive IgVH genes, and the expression of a set of NF-κB pathway genes, including TRAF5, REL, and PKCA. (Blood. 2005;106:1831-1838)

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Abstract 906: Development of novel preclinical models of secondary resistance downstream B cell receptor in marginal zone lymphoma

10.1158/1538-7445.am2018-906 ◽

2018 ◽

Author(s):

Alberto J. Arribas ◽

Eugenio Gaudio ◽

Luciano Cascione ◽

Chiara Tarantelli ◽

Antonella Zucchetto ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

B Cell Receptor ◽

Preclinical Models ◽

Secondary Resistance

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Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma

Cancers ◽

10.3390/cancers12061669 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1669

Author(s):

Jiwon Koh ◽

Insoon Jang ◽

Seongmin Choi ◽

Sehui Kim ◽

Ingeon Jang ◽

...

Keyword(s):

B Cell ◽

High Throughput Sequencing ◽

Marginal Zone ◽

Progression Free Survival ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

Ki 67 ◽

Genetic Characteristics ◽

Recurrent Mutations ◽

Nodal Marginal Zone Lymphoma

Nodal marginal zone lymphoma (NMZL) is a rare B-cell neoplasm, the genetic and transcriptomic landscape of which are unclear. Using high-throughput sequencing for whole-exome and transcriptome, we investigated the genetic characteristics of NMZL in a discovery cohort (n = 8) and validated their features in an extended cohort (n = 30). Novel mutations in NFKBIE and ITPR2 were found in 7.9% (3/38) and 13.9% (5/36), respectively, suggesting roles for the NF-κB pathway and B-cell-receptor-mediated calcium signaling pathway in the pathogenesis of NMZL. RNA-seq showed that NMZLs were characterized by an aberrant marginal zone differentiation, associated with an altered IRF4-NOTCH2 axis and the enrichment of various oncogenic pathways. Based on gene expression profile, two subgroups were identified. Compared with subgroup 1, subgroup 2 showed the following: the significant enrichment of cell cycle-associated and MYC-signaling pathways, a more diverse repertoire of upstream regulators, and higher Ki-67 proliferation indices. We designated two subgroups according to Ki-67 labeling, and subgroup 2 was significantly associated with a shorter progression-free survival (p = 0.014), a greater proportion of large cells (p = 0.009), and higher MYC expression (p = 0.026). We suggest that NMZL has unique features and, in this study, we provide information as to the heterogeneity of this enigmatic entity.

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

Blood ◽

10.1182/blood.v108.11.2422.2422 ◽

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.

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Absence of Mutations of the Histone Methyltransferase Gene EZH2 In Splenic B-Cell Marginal Zone Lymphoma

Blood ◽

10.1182/blood.v116.21.5086.5086 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5086-5086

Author(s):

Luz Martínez-Avilés ◽

Marta Salido ◽

Beatriz Bellosillo ◽

Vera Adema ◽

Ana Ferrer ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Mutational Analysis ◽

Conflicts Of Interest ◽

Direct Sequencing ◽

Normal Karyotype ◽

Marginal Zone Lymphoma ◽

Low Grade ◽

Splenic Marginal Zone Lymphoma ◽

7Q Deletion

Abstract Abstract 5086 Background Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoproliferative disorder with characteristic clinical, cytological, histological and immunophenotypical features. The most common cytogenetic abnormality, present in 30–40% of the patients is the 7q deletion, that extends from 7q21 to 7q36. This aberration may represent a primary pathogenic event in SMZL. Recently, mutations in the EZH2 gene, located at 7q36.1, have been described in different hematological malignancies including B-cell lymphomas. However, the role of the EZH2 gene in SMZL has to be elucidated. Aim To determine the prevalence of EZH2 mutations in a cohort of SMZL patients. Patients and Methods Twenty-nine patients with SMZL were screened for mutations in the EZH2 gene. From the whole cohort, 11 patients presented 7q deletion (three of them as a single anomaly), 11 had a normal karyotype and 7 had other cytogenetic aberrations. The mutational analysis of the EZH2 gene was performed by direct sequencing using primers covering the whole exome of the gene. DNA was extracted from CD19 isolated B-cells from peripheral blood or from total lymphocytes if the percentage of pathologic B-cell was higher than 50%. Results From the whole cohort of 29 SMZL patients, no pathogenic mutations (frameshift or nonsense mutations) were detected in the EZH2 gene in any of the patients analyzed. Five patients harboured the missense mutation D185H in exon 6, that has been previously described as a single nucleotide polymorphism (SNP). Conclusions In conclusion, the EZH2 gene is not mutated in our series of SMZL patients suggesting that this gene is not involved in the pathogeny of this entity. Acknowledgments: Fellowship FI2008 (AGAUR) to LMA, This work was supported (in part) by grants from Instituto de Salud Carlos III FEDER; Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER): RD06/0020/0031 and RD07/0020/2004; Ministerio de Sanidad y Consumo (Spain): PI07/0586. Disclosures: No relevant conflicts of interest to declare.

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Prevalence and Clinical Significance of the MYD88 (L265P) Somatic Mutation in Patients with Waldenström Macroglobulinemia, IgM-Monoclonal Gammopathy of Undetermined Significance or Other Mature B-Cell Neoplasms.

Blood ◽

10.1182/blood.v120.21.2667.2667 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2667-2667 ◽

Cited By ~ 1

Author(s):

Marzia Varettoni ◽

Luca Arcaini ◽

Silvia Zibellini ◽

Emanuela Boveri ◽

Sara Rattotti ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Lymphoproliferative Disorders ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Specific Pcr ◽

Allele Specific ◽

Myd88 L265p Mutation ◽

Myd88 L265p ◽

Monoclonal Component

Abstract Abstract 2667 Waldenström Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration by lymphoplasmacytic lymphoma associated with a monoclonal component of IgM type in the serum. WM is often preceded by an IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). The cumulative probability of progression of IgM-MGUS to WM or to other lymphoproliferative disorders is approximately 1.5% per year. Other mature B-cell neoplasms such as splenic marginal zone lymphoma (SMZL) and B-cell chronic lymphoproliferative disorders (B-CLPD) can carry an IgM monoclonal component and should therefore be considered in differential diagnosis with WM. In a study based on parallel sequencing of the whole genome of lymphoplasmacytic cells and paired normal tissue from WM patients, Treon et al (Blood. 2011;118:Abstract 300) have identified a highly recurrent somatic mutation with oncogenic activity in the myeloid differentiation primary response (MYD88) gene, leading to a change from leucine to proline at position 265 of the aminoacid sequence [MYD88 (L265P)]. Targeted Sanger resequencing showed MYD88 (L265P) in 90% of WM patients, but only in a minority of patients with IgM-MGUS or other mature B-cell neoplasms such as SMZL. We developed an allele-specific PCR for the MYD88 (L265P) mutation, and studied 58 patients with WM, 77 with IgM-MGUS, 84 with splenic marginal zone lymphoma (SMZL) and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). DNA was obtained from bone marrow cells (n=204) and peripheral blood (n=67). The aims of this study were: i) to assess the prevalence of the mutation in WM, IgM-MGUS, SMZL, and B-CLPD; ii) to analyze the relationship between MYD88 (L265P) mutation and clinical phenotype; iii) to evaluate the impact of the mutation on the risk of progression from IgM-MGUS WM or other lymphoproliferative disorders. The MYD88 (L265P) mutation was detected in 58/58 (100%) patients with WM, either asymptomatic (n=39) or symptomatic (n=18), and in 36/77 (47%) patients with IgM-MGUS. In addition, it was detected in 5/84 (6%) patients with SMZL and in 3/52 (6%) with B-CLPD; of these MYD88 (L265P)-positive subjects, 4 SMZL and 2 B-CLPD patients carried a serum IgM monoclonal component, while the remaining B-CLPD patient carried a double (IgM and IgG) monoclonal component. Compared with IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) had significantly higher levels of IgM (P<.0001), lower levels of IgG (P=.04) and IgA (P=.04), and higher incidence of Bence-Jones proteinuria at diagnosis (P=.002). During the follow-up, 9 patients with IgM-MGUS progressed to WM (7 cases) or to marginal zone lymphoma (2 cases). Using a case-control approach, the risk of evolution of patients with MYD88 (L265P) was significantly higher as compared to that of patients with wild-type MYD88 sequence (OR 4.7, 95% confidence interval 0.8–48.7, P=.047). In conclusion, the findings of this study indicate that: i) the allele-specific PCR we developed is able to detect the MYD88 (L265P) mutation in all patients with WM and in nearly half the patients with IgM-MGUS, and therefore represents a useful diagnostic tool; ii) MYD88 (L265P) is an uncommon molecular lesion in SMZL and in B-CLPD, but is associated with an IgM monoclonal component in the few positive patients, suggesting that some cases of B-CLPD might be included in the spectrum of WM; iii) in IgM-MGUS, the mutation is associated with greater disease burden and higher risk of disease progression, and therefore represents a useful prognostic marker. Disclosures: No relevant conflicts of interest to declare.

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Mutational Status of Splenic Marginal Zone Lymphoma Revealed by Whole Exome Sequencing.

Blood ◽

10.1182/blood.v120.21.2698.2698 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2698-2698

Author(s):

Nerea Martinez ◽

Ignacio Varela ◽

Jose P. Vaque ◽

Sophia Derdak ◽

Sergi Beltran ◽

...

Keyword(s):

B Cell ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Peripheral Blood ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Mutational Status ◽

Whole Exome ◽

Splenic Tumor

Abstract Abstract 2698 Background: Splenic marginal zone lymphoma (SMZL) is a small B cell neoplasm whose molecular pathogenesis is still unknown. It has a relatively indolent course, but a fraction of the cases may show an aggressive behavior. The lack of comprehensive molecular analysis for SMZL precludes the development of targeted therapy. Here we studied the mutational status of 6 SMZL samples using Whole Exome Next Generation Sequencing. Methods: Genomic DNA was extracted from splenic tumor or peripheral blood samples and oral mucosa as the corresponding non-tumor control. Whole exome sequencing was performed at CNAG (Barcelona, Spain) following standard protocols for high-throughput paired-end sequencing on the Illumina HiSeq2000 instruments (Illumina Inc., San Diego, CA). The variant calling was performed using an in house written software calling potential mutations showing a minimum independent multi-aligner evidence. Results: We performed paired-end-76pb whole exome sequencing on 6 SMZL samples and the corresponding normal counterpart. Three of the samples corresponded to CD19 isolated cells from peripheral blood, while other three corresponded to spleen freshly frozen tissue. The mean coverage obtained was 104.07 (82.46–119.59) with a mean of 91.41% (90.41–93.73) of bases with at least 15× coverage. After filtering, 237 substitutions and 21 indels where obtained. No recurrent variation was found. Six of the variations found here were already described in other malignancies. Variations were classified into silent (75), missense (147), nonsense (8), and essential splice (5), according to their potential functional effect, and into tolerated (54) and deleterious (76) according to the “variant effect predictor” tool of Ensembl Genome Browser. Whole exome sequencing permitted us to identify variations in several genes of TLR/NFkB pathway (Myd88, Peli3), BCR (Myd88, Arid3A) or signal transduction (ARHGAP32), essential pathways for B-cell differentiation. These variations and other involving selected genes, such as the Bcl6 repressor BCOR, were validated by capillary sequencing. These results were confirmed and expanded in a second series of 10 new cases by exome sequencing. Conclusions: SMZL samples contain somatic mutation involving genes regulating BCR signaling, TLR/NFKB pathways and chromatin remodeling. Disclosures: No relevant conflicts of interest to declare.

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