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

Haematologica ◽

10.3324/haematol.2010.025437 ◽

2010 ◽

Vol 95 (10) ◽

pp. 1792-1796 ◽

Cited By ~ 58

Author(s):

S. Zibellini ◽

D. Capello ◽

F. Forconi ◽

P. Marcatili ◽

D. Rossi ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

B Cell Receptor ◽

Splenic Marginal Zone Lymphoma

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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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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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Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

Nature Communications ◽

10.1038/ncomms11889 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 21

Author(s):

Eloy F. Robles ◽

Maria Mena-Varas ◽

Laura Barrio ◽

Sara V. Merino-Cortes ◽

Péter Balogh ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Cell Receptor ◽

B Cell Receptor ◽

Receptor Signalling

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Overexpression of TOSO in CLL Is Triggered by B-Cell Receptor Signaling and Associated with Progressive Disease.

Blood ◽

10.1182/blood.v112.11.2070.2070 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2070-2070

Author(s):

Christian P Pallasch ◽

Alexandra Schulz ◽

Nadine Kutsch ◽

Janine Schwamb ◽

Susanne Hagist ◽

...

Keyword(s):

Flow Cytometry ◽

B Cells ◽

B Cell ◽

Healthy Donor ◽

Progressive Disease ◽

Marginal Zone ◽

Cell Receptor ◽

B Cell Receptor ◽

Quantitative Real Time Pcr ◽

Follicular Lymphomas

Abstract Resistance towards apoptotic stimuli mediated by overexpression of antiapoptotic factors or extracellular survival signals like B-cell receptor stimulation (BCR) are considered to be responsible for accumulation of malignant B cells in CLL . TOSO, also known as Fas-inhibitory molecule 3 (FAIM3), was identified as overexpressed candidate gene in CLL based on re-evaluation of publicly available microarray data sets. Based on primary CLL samples from 106 patients, TOSO expression was compared to healthy donor B cells using quantitative real-time PCR, western-blot, flow cytometry and immunohistochemistry. To reveal underlying mechanisms of TOSO overexpression, B-cell receptor (BCR) and CD40Ligand stimulation as well as bone marrow stroma cell co-incubation was performed. Apoptotic resistance was assessed by annexin V/7-AAD flow cytometry in context of CH11-Fas-agonistic antibody. TOSO was identified to exhibit elevated relative expression of 6.8 compared to healthy donor B cells using quantitative real-time PCR (p=0.004). High levels of TOSO expression in CLL correlated with high leukocyte count, advanced Binet stage, previous need for chemotherapy and unmutated IgVH status. CD38+ CLL subsets harboring proliferative activity showed significantly enhanced TOSO expression. Immunohistochemistry revealed upregulation of TOSO in lymph nodes of CLL patients. In lymph nodes derived from healthy donors TOSO was detected in single plasmocytoid cells within the germinal center and in the marginal zone. No specific staining was seen in follicular lymphomas. CLL-specific upregulation of TOSO was confirmed by RT-PCR, samples of follicular lymphomas, DLBCL, marginal zone lymphoma and Hodgkin cell lines did not reveal TOSO up-regulation. We evaluated functional mechanisms of aberrant TOSO expression in CLL cells and identified TOSO expression significantly being induced by BCR-stimulation compared to control cells (relative expression (RE) 8.25 vs. 4.86, p=0.013). In contrast, CD40L signaling significantly reduced TOSO expression (RE 2.60; p=0.007). Spontaneous apoptosis of CLL cells was significantly reduced by BCR-stimulus, in CD40Ligandstimulated CLL samples a slight sensitization towards Fas-mediated apoptosis was seen. In summary, we show that the anti-apoptotic factor TOSO is associated with progressive disease and enhanced in the proliferative CD38+ cell subset. Both association with unmutated IgVH and the specific induction of TOSO via the BCR suggest autoreactive BCR signaling as a key mediator of apoptosis resistance in CLL. Down-regulation of TOSO by CD40Ligand in the context of CD40Ligand-mediated Fas-sensitization of CLL reveal TOSO as a new anti-apoptotic factor in CLL. CLL-specific over-expression of the transmembrane protein might further offer new therapeutic strategies in CLL treatment.

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DEVELOPMENT OF NOVEL PRECLINICAL MODELS OF SECONDARY RESISTANCE TO THE PI3KΔ INHIBITOR IDELALISIB IN SPLENIC MARGINAL ZONE LYMPHOMA (SMZL)

Hematological Oncology ◽

10.1002/hon.2438_119 ◽

2017 ◽

Vol 35 ◽

pp. 254-254

Author(s):

A.J. Arribas ◽

E. Gaudio ◽

A. Rinaldi ◽

L. Cascione ◽

C. Tarantelli ◽

...

Keyword(s):

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Preclinical Models ◽

Secondary Resistance

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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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