Expression of B-cell activating factor, a proliferating inducing ligand and its receptors in primary central nervous system lymphoma

B-cell activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferating inducing ligand (APRIL) might play an important role in the pathogenesis of systemic B-cell malignancies. However, the BAFF/APRIL system has not been systematically evaluated in primary central nervous system lymphoma (PCNSL) to date. We assessed the expression of BAFF, APRIL and its receptors BAFF-R (BAFF receptor), BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator cyclophilin ligand interactor) in five PCNSL specimens by immunohistochemical staining. We found extensive expression of BAFF and weak to moderate expression of APRIL, BAFF-R, BCMA, and TACI in all specimens. CD20 positive cells showed expression of both ligands and receptors at the same time. Our results indicate that autocrine stimulation of the BAFF/APRIL system might be involved in the pathogenesis of PCNSL.

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Association of serum B cell activating factor from the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) with central nervous system and renal disease in systemic lupus erythematosus

Lupus ◽

10.1177/0961203313496302 ◽

2013 ◽

Vol 22 (9) ◽

pp. 873-884 ◽

Cited By ~ 49

Author(s):

FB Vincent ◽

M Northcott ◽

A Hoi ◽

F Mackay ◽

EF Morand

Keyword(s):

Systemic Lupus Erythematosus ◽

Central Nervous System ◽

Nervous System ◽

Renal Disease ◽

B Cell ◽

Lupus Erythematosus ◽

Tumour Necrosis ◽

Systemic Lupus ◽

B Cell Activating Factor ◽

Necrosis Factor

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Maturation of Marginal Zone and Follicular B Cells Requires B Cell Activating Factor of the Tumor Necrosis Factor Family and Is Independent of B Cell Maturation Antigen

Journal of Experimental Medicine ◽

10.1084/jem.194.11.1691 ◽

2001 ◽

Vol 194 (11) ◽

pp. 1691-1698 ◽

Cited By ~ 168

Author(s):

Pascal Schneider ◽

Hisakazu Takatsuka ◽

Anne Wilson ◽

Fabienne Mackay ◽

Aubry Tardivel ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Tumor Necrosis ◽

Marginal Zone ◽

Cell Maturation ◽

Soluble Form ◽

B Cell Maturation ◽

B Cell Activating Factor ◽

Necrosis Factor ◽

B Cell Maturation Antigen

B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way.

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Targeting the PI3K/AKT/mTOR Signaling Pathway in Primary Central Nervous System Lymphoma: Current Status and Future Prospects

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200517112252 ◽

2020 ◽

Vol 19 (3) ◽

pp. 165-173

Author(s):

Xiaowei Zhang ◽

Yuanbo Liu

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Signaling Pathway ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Antitumor Effects ◽

Term Survival

Primary Central Nervous System Lymphoma (PCNSL) is a rare invasive extranodal non- Hodgkin lymphoma, a vast majority of which is Diffuse Large B-Cell Lymphoma (DLBCL). Although high-dose methotrexate-based immunochemotherapy achieves a high remission rate, the risk of relapse and related death remains a crucial obstruction to long-term survival. Novel agents for the treatment of lymphatic malignancies have significantly broadened the horizons of therapeutic options for PCNSL. The PI3K/AKT/mTOR signaling pathway is one of the most important pathways for Bcell malignancy growth and survival. Novel therapies that target key components of this pathway have shown antitumor effects in many B-cell malignancies, including DLBCL. This review will discuss the aberrant status of the PI3K/AKT/mTOR signaling pathways in PCNSL and the application prospects of inhibitors in hopes of providing alternative clinical therapeutic strategies and improving prognosis.

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Primary Central Nervous System Lymphoma Mimicking Longitudinally Extensive Transverse Myelitis

The Neurohospitalist ◽

10.1177/1941874420967560 ◽

2020 ◽

pp. 194187442096756

Author(s):

Prashant Anegondi Natteru ◽

Shashank Shekhar ◽

Lakshmi Ramachandran Nair ◽

Hartmut Uschmann

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Oligoclonal Bands ◽

Relative Reduction ◽

Thalamic Lesion ◽

The Right

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extra-nodal non-Hodgkin’s lymphoma. Three regions can be involved in PCNSL: the brain, the spine, or the vitreus and retina. Spinal PCNSL is rare. It can mimic neoplasm, infection, and inflammation. Diagnostic confirmation is by tissue biopsy, and even then, tissue corroboration may be altered by an inflammatory overlay. We report a 59-year-old woman who we saw after she had 4 weeks of ascending tetraparesis plus bowel and bladder incontinence. Upon presentation, the patient was ventilator-dependent and locked-in. She reported normal sensation through eye-blinking. Magnetic resonance imaging (MRI) brain revealed signal intensity in the bilateral corona radiata and restricted diffusion in the right thalamus, whereas, MRI cervical, and thoracic spine showed T2 prolongation in the anterior medulla and upper cervical cord, with enhancement to C2-C3, and long segment hyperintensity from T1-T9 levels, respectively, suggestive of neuromyelitis optica spectrum disorder. Cerebrospinal fluid cytomorphology and flow cytometry were inconclusive for lymphoma/leukemia, but oligoclonal bands were present. Serum aquaporin-4 (AQP-4) antibodies were negative. MR spectroscopy demonstrated NAA reduction, mild lipid lactate peak, and relative reduction of choline on the side of the lesion, favoring demyelination. She received 5-days of intravenous methylprednisolone, followed by 7 sessions of plasma exchange without clinical improvement. Stereotactic biopsy of the right thalamic lesion revealed diffuse large B-cell lymphoma. PCNSL can mimic a demyelinating process early on, as steroid treatment could disrupt B-cell lymphoma cells, thus masking the correct diagnosis.

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T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presenting as a Primary Central Nervous System Lymphoma

Rare Tumors ◽

10.4081/rt.2015.6084 ◽

2015 ◽

Vol 7 (4) ◽

pp. 160-162 ◽

Cited By ~ 1

Author(s):

Pooja Advani ◽

Jason Starr ◽

Abhisek Swaika ◽

Liuyan Jiang ◽

Yushi Qiu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Pathway analysis of primary central nervous system lymphoma

Blood ◽

10.1182/blood-2007-10-119099 ◽

2008 ◽

Vol 111 (6) ◽

pp. 3200-3210 ◽

Cited By ~ 106

Author(s):

Han W. Tun ◽

David Personett ◽

Karen A. Baskerville ◽

David M. Menke ◽

Kurt A. Jaeckle ◽

...

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Pathway Analysis ◽

Metastatic Cancer ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Significant Differential Expression ◽

A Genome

Abstract Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true “CNS signature” because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

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Single cell transcriptomic analysis of diffuse large B cells in cerebrospinal fluid of central nervous system lymphoma

10.1101/2020.04.18.20065805 ◽

2020 ◽

Author(s):

Haoyu Ruan ◽

Zhe Wang ◽

Yue Zhai ◽

Ying Xu ◽

Linyu Pi ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

B Cells ◽

B Cell ◽

Single Cell ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Great Promise ◽

Leptomeningeal Involvement

AbstractDiffuse large B-cell lymphoma (DLBCL) is the predominant type of central nervous system lymphoma (CNSL) including primary CNSL and secondary CNSL. Diffuse large B cells in cerebrospinal fluid (CSF-DLBCs) have offered great promise for the diagnostics and therapeutics of CNSL leptomeningeal involvement. To explore the distinct phenotypic states of CSF-DLBCs, we analyzed the transcriptomes of 902 CSF-DLBCs from six CNSL-DLBCL patients using single-cell RNA sequencing technology. We defined CSF-DLBCs based on abundant expression of B-cell markers, as well as the enrichment of cell proliferation and energy metabolism pathways. CSF-DLBCs within individual patients exhibited monoclonality with similar variable region of light chains (VL) expression. It is noteworthy that we observed some CSF-DLBCs have double classes of VL (lambda and kappa) transcripts. We identified substantial heterogeneity in CSF-DLBCs, and found significantly greater among-patient heterogeneity compared to among-cell heterogeneity within a given patient. The transcriptional heterogeneity across CSF-DLBCs is manifested in cell cycle state and cancer-testis antigens expression. Our results will provide insight into the mechanism research and new diagnostic direction of CNSL-DLBCL leptomeningeal involvement.

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Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2020.7667 ◽

2020 ◽

Vol 18 (11) ◽

pp. 1571-1578

Author(s):

Matthias Holdhoff ◽

Maciej M. Mrugala ◽

Christian Grommes ◽

Thomas J. Kaley ◽

Lode J. Swinnen ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Central Nervous System Lymphoma ◽

High Dose Chemotherapy ◽

High Dose ◽

Newly Diagnosed ◽

Phase Ii Trials ◽

Whole Brain Radiation ◽

The Central Nervous System

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3–8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX–based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX–based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

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