scholarly journals Relevant Cytokines in the B Cell Lymphoma Micro-Environment

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2525
Author(s):  
Günter Krause ◽  
Floyd Hassenrück ◽  
Michael Hallek
Keyword(s):  
B Cell ◽  
Cytokine Production ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Blood Levels ◽  
Stromal Fibroblasts

Cytokines are soluble protein factors with importance in intercellular communication and, as such, play pivotal roles in the pathogenesis of B cell malignancies. Evidence from in vitro cultures permitted us to choose example cytokines that bind to different biochemical receptor types. Activated malignant B cells or stromal fibroblasts and macrophages prominently secrete the chemokines CCL3 or CXCL12 and CXCL13, respectively. Apart from helper T cells, various cell types of the B cell lymphoma microenvironment are capable of producing the cytokines IL-4, IL-6, IL-10 and TNFα. Owing to its impact on the development of myeloid cells, CSF-1 is among important soluble factors in the B cell lymphoma microenvironment. Inhibitors of B cell receptor-associated kinases often act via the blockade of cytokine production, but also prevent cytokine effects, e.g., chemotaxis. Increments in blood levels in chronic lymphocytic leukemia patients compared to healthy donors and normalization upon treatment with ibrutinib can be explained by producing cell types and modulation of cytokine production observed in vitro.

scholarly journals Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Kamil Bojarczuk ◽  
Kirsty Wienand ◽  
Jeremy A. Ryan ◽  
Linfeng Chen ◽  
Mariana Villalobos-Ortiz ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Xenograft Model ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Synergistic Activity ◽  
Genetic Bases

Abstract Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1–dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2–mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

Phospho-SFKs (Y416) As a Potential Predictive Marker for Dasatinib Therapy in B-Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3727-3727
Author(s):  
Xiaoxian Zhao ◽  
Eric D. Hsi
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Predictive Marker ◽  
Lymphocytic Leukemia ◽  
Lymphoma Cell ◽  
Raji Cells ◽  
B Lymphoma ◽  
Induced Apoptosis

Abstract Abstract 3727 The Src family of protein tyrosine kinases (SFKs) plays an important role in regulating multiple signaling networks including B-cell receptors (BCR) mediated pathways and abnormal SFK kinase activation promotes B lymphoma cell survival. Dasatinib is an oral BCR/ABL1 and SKF inhibitor useful in the treatment of imatinib-resistant CML and Ph+ALL. Given its broad inhibitory activity, dasatinib may be useful in the treatment of other hematologic malignancies and having a biologic predictor of response would be helpful in rational selection of this targeted therapeutic. We hypothesized this agent could have therapeutic potential against lymphoma patients with p-SFK (Y416) expression. Constitutive p-SFK (Y416) expression (indicating active SFK signaling) was detected in both B-lymphoma cell lines and a subset of primary lymphoma tissues including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Burkitt lymphoma and small lymphocytic leukemia (SLL). Dasatinib induced apoptosis of B-lymphoma Raji cells correlated with high level expression of constitutive p-SFK (Y416) and dasatinib rapidly reduced the global level of tyrosine phosphorylations including p-SFK (Y416) in Raji cells. 19 of 28 lymphoma cases (67.9%) were positive for p-SFK (Y416) by Western blot analysis. Dasatinib displayed in vitro dose-dependent (10–200 nM) killing activity against 17 of those 19 p-SFK (Y416) cases (89.5%). In contrast, only 2 of 9 p-SFK (Y416) negative cases (22.2%) had response to dasatinib exposure. Thus presence of p-SFK (Y416) was associated with in vitro response to dasatinib (p <0.0001). Similar to tested Raji cells, dasatinib induced apoptosis of primary B-cell lymphoma cells was accompanied with de-phosphorylation of p-SFK (Y416) and cleavage of caspase-3. 6 of 9 tested CLL cases were p-SFK (Y416) positive. Dasatinib displayed in vitro killing activities against 5 of 6 positive cases with a range of killing from 12% to 53% (mean 26.5%) of malignant B-cells. Meanwhile, one of three negative cases showed response to dasatinib (17% killing). We conclude that p-SFK (Y416) may be a useful predictive marker of response to dasatinib. Potential uses include pharmacodynamic monitoring or integral biomarker for selecting appropriate patients with B-cell malignancies for clinical trials. Disclosures: No relevant conflicts of interest to declare.

Cyclin-Dependent Kinase Inhibitor Seliciclib Shows In Vitro Activity in Diffuse Large B Cell Lymphomas.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4738-4738
Author(s):  
Francesco Bertoni ◽  
Katia Lacrima ◽  
Andrea Rinaldi ◽  
Sara Vignati ◽  
Vittoria Martin ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Active Agent ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Large B Cell

Abstract Background. Despite recent improvements in treatment, a significant fraction of patients with diffuse large B cell lymphoma (DLBCL) still fail therapy. Therefore, new therapeutic modalities are needed to advance the cure rate. Seliciclib (CYC202, R-roscovitine) is a purine analogue developed as an inhibitor of CDK2/cyclin E CDK7/cyclin H and CDK9/cyclin T. Seliciclib has been shown to be active in B cell neoplasms, such as mantle cell lymphoma, chronic lymphocytic leukemia and in multiple myeloma in vitro. The aim of this study was to assess the in vitro activity of seliciclib in DLBCL. Materials and methods. The anti-proliferative activity of seliciclib was tested in nine human DLBCL cell lines and six DLBCL primary cell cultures. The effects of seliciclib on the cell cycle and on apoptosis, as well as on transcription-related proteins were assessed. Results. The cell viability of all DLBCL cell lines and primary cells was reduced by seliciclib treatment. The IC50 for the cell lines ranged from 13 to 36 μM. The effect of seliciclib was independent of the genetic aberrations characterizing the cell lines. After seliciclib exposure cells accumulated in G2/M or in G1 phase, with most of the cells showing signs of apoptosis. Despite the clear cytotoxic effect and induction of apoptosis, we could not identify a unique mechanism of action. Conclusions. Our in vitro data suggest that seliciclib is an active agent in DLBCL. Its efficacy is apparently independent of the underlying chromosomal translocations characteristic of DLBCL. The drug might represent a new therapeutic agent in this lymphoma subtype.

scholarly journals Role of Specific B-Cell Receptor Antigens in Lymphomagenesis

2020 ◽  
Vol 10 ◽  
Author(s):  
Lorenz Thurner ◽  
Sylvia Hartmann ◽  
Frank Neumann ◽  
Markus Hoth ◽  
Stephan Stilgenbauer ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Plasma Cell Dyscrasia ◽  
Gastric Malt Lymphoma

The B-cell receptor (BCR) signaling pathway is a crucial pathway of B cells, both for their survival and for antigen-mediated activation, proliferation and differentiation. Its activation is also critical for the genesis of many lymphoma types. BCR-mediated lymphoma proliferation may be caused by activating BCR-pathway mutations and/or by active or tonic stimulation of the BCR. BCRs of lymphomas have frequently been described as polyreactive. In this review, the role of specific target antigens of the BCRs of lymphomas is highlighted. These antigens have been found to be restricted to specific lymphoma entities. The antigens can be of infectious origin, such as H. pylori in gastric MALT lymphoma or RpoC of M. catarrhalis in nodular lymphocyte predominant Hodgkin lymphoma, or they are autoantigens. Examples of such autoantigens are the BCR itself in chronic lymphocytic leukemia, LRPAP1 in mantle cell lymphoma, hyper-N-glycosylated SAMD14/neurabin-I in primary central nervous system lymphoma, hypo-phosphorylated ARS2 in diffuse large B-cell lymphoma, and hyper-phosphorylated SLP2, sumoylated HSP90 or saposin C in plasma cell dyscrasia. Notably, atypical posttranslational modifications are often responsible for the immunogenicity of many autoantigens. Possible therapeutic approaches evolving from these specific antigens are discussed.

Cerebral aspergillosis in a patient on ibrutinib therapy—A predisposition not to overlook

2018 ◽  
Vol 25 (6) ◽  
pp. 1486-1490 ◽  
Author(s):  
Muhammad Salman Faisal ◽  
Hira Shaikh ◽  
Ahmed Khattab ◽  
Mary Albrethsen ◽  
Salman Fazal
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Rare Complication ◽  
B Cell Lymphoma ◽  
Complete Recovery ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Receptor Signaling

Ibrutinib has revolutionized the treatment of B-cell malignancies since its approval for chronic lymphocytic leukemia. It is also used in mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstrom’s macroglobulinemia, among others. It is a Bruton’s tyrosine kinase inhibitor that acts on B-cell receptor signaling pathway and predisposes to various infections due to its effects on neutrophils, monocytes and T cells. We present a case of cerebral invasive aspergillosis in a patient being treated with ibrutinib for relapsed chronic lymphocytic leukemia. It was hard to associate the condition to ibrutinib versus the chronic lymphocytic leukemia. The patient was successfully treated with a combination of voriconazole and micafungin, resulting in complete recovery and no residual deficits. This highlights the importance of recognizing the rare complication in those on ibrutinib and initiating the treatment immediately with appropriate antifungal agents to improve prognosis of this potentially fatal condition.

scholarly journals Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1396 ◽  
Author(s):  
Dimitar G. Efremov ◽  
Sven Turkalj ◽  
Luca Laurenti
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Receptor Activation ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Downstream Signaling ◽  
Pathway Activation

The B cell receptor (BCR) pathway has been identified as a potential therapeutic target in a number of common B cell malignancies, including chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B cell lymphoma, and Waldenstrom’s macroglobulinemia. This finding has resulted in the development of numerous drugs that target this pathway, including various inhibitors of the kinases BTK, PI3K, and SYK. Several of these drugs have been approved in recent years for clinical use, resulting in a profound change in the way these diseases are currently being treated. However, the response rates and durability of responses vary largely across the different disease entities, suggesting a different proportion of patients with an activated BCR pathway and different mechanisms of BCR pathway activation. Indeed, several antigen-dependent and antigen-independent mechanisms have recently been described and shown to result in the activation of distinct downstream signaling pathways. The purpose of this review is to provide an overview of the mechanisms responsible for the activation of the BCR pathway in different B cell malignancies and to correlate these mechanisms with clinical responses to treatment with BCR inhibitors.

In Vitro Activity of SYK and BCR-ABL Inhibitors in Aggressive Lymphomas.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2520-2520
Author(s):  
Francesco Bertoni ◽  
Andrea Rinaldi ◽  
Anna Sasso ◽  
Gianluca Gaidano ◽  
Emanuele Zucca ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Viable Cell Number ◽  
Primary Cells ◽  
Aggressive Lymphomas

Abstract The B cell receptor tyrosine kinase SYK is a critical component of the B-cell receptor signalling pathway in normal B cells. We have recently reported that SYK is amplified and over-expressed in mantle cell lymphoma (MCL) and that the growth of MCL and diffuse large B cell lymphoma (DLBCL) cell lines over-expressing SYK is inhibited by piceatannol, a known SYK inhibitor (Bertoni et al, ASH 2005; Rinaldi et al, BJH 2006). Others have reported important SYK expression in splenic marginal zone B cell lymphomas, in DLBCL and peripheral T cell lymphomas (PTCL) (Ruiz-Ballesteros et al, 2005; Mahadevan et al, w Streubel et al, 2006), suggesting SYK targeting agents could be useful for the treatment of various lymphoma subtypes. SYK inhibitors are already in clinical development for treatment of asthma. Here, we report on the activity on lymphoma cell lines and primary cells of the SYK/ZAP-70 inhibitor #1 (Novartis) and of the BCR-ABL inhibitors imatinib (Novartis) and nilotinib (Novartis), which could act as cross-selecting SYK inhibitors (Atwell et al, 2004). We treated four human MCL and three DLBCL established cell lines with increasing doses of the SYK/ZAP-70 inhibitor #1, imatinib and nilotinib for 72 h. Cell viability was measured with the MTT assay. The two cell lines expressing high levels of SYK, JeKo-1 and SUD-HL-6, were sensitive to the compounds (IC50: Syk/ZAP-70 inhibitor #1, 1–5 μM; imatinib, 15–20 μM; nilotinib, 10 μM). Cells with lower SYK expression were generally less sensitive to all three compounds. To obtain further data on the relevance of SYK inhibition in lymphoma, we treated nine lymphoma primary cells with the piceatannol (Sigma), the SYK/ZAP-70 inhibitor #1 and nilotinib. Responses, defined as <50% decrease in viable cell number, were observed with piceatannol (4/9 samples), the Syk/ZAP-70 inhibitor #1 (3/9 samples) and nilotinib (3/9 samples). Immunoblotting experiments aimed to elucidate the mechanism of action are under-way and data will be presented at the meeting. In conclusion, our data indicate that pharmacological inhibition of SYK is a therapeutic approach to be further investigated in subsets of aggressive lymphomas.

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