scholarly journals The B-cell receptor signaling pathway as a therapeutic target in CLL

Blood ◽  
2012 ◽  
Vol 120 (6) ◽  
pp. 1175-1184 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Amy J. Johnson ◽  
John C. Byrd
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Myeloid Leukemia ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Therapeutic Targeting ◽  
Bcr Signaling

Abstract Targeted therapy with imatinib and other selective tyrosine kinase inhibitors has transformed the treatment of chronic myeloid leukemia. Unlike chronic myeloid leukemia, chronic lymphocytic leukemia (CLL) lacks a common genetic aberration amenable to therapeutic targeting. However, our understanding of normal B-cell versus CLL biology points to differences in properties of B-cell receptor (BCR) signaling that may be amenable to selective therapeutic targeting. The applica-tion of mouse models has further expanded this understanding and provides information about targets in the BCR signaling pathway that may have other important functions in cell development or long-term health. In addition, overexpression or knockout of selected targets offers the potential to validate targets genetically using new mouse models of CLL. The initial success of BCR-targeted therapies has promoted much excitement in the field of CLL. At the present time, GS-1101, which reversibly inhibits PI3Kδ, and ibrutinib (PCI-32765), an irreversible inhibitor of Bruton tyrosine kinase, have generated the most promising early results in clinical trials including predominately refractory CLL where durable disease control has been observed. This review provides a summary of BCR signaling, tools for studying this pathway relevant to drug development in CLL, and early progress made with therapeutics targeting BCR-related kinases.

An HSP90 Inhibitor, PU-H71, Antagonizes Stroma-Induced Pro-Survival Effects in CLL through Its Inhibition of Multi-Component B-Cell Receptor Signaling Pathway

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5289-5289
Author(s):  
Ailin Guo ◽  
Pin Lu ◽  
Chaojie Zhen ◽  
Gabriela Chiosis ◽  
Yue Lynn Wang
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Cell Receptor ◽  
Hsp90 Inhibitor ◽  
B Cell Receptor ◽  
Receptor Signaling ◽  
Bcr Signaling ◽  
Receptor Signaling Pathway ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

Abstract Background: Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B-cells in the hematopoietic system. The B-cell receptor (BCR) plays an essential role in the pathogenesis of CLL and many components of the BCR signaling pathway are known clients of HSP90. HSP90 is a highly conserved molecular chaperone that ensures the proper folding and stabilization of its client proteins. In this study, we investigated whether PU-H71 a novel purine-scaffold HSP90 Inhibitor, has anti-tumor activity in CLL by destabilizing BCR signaling pathway constituents. Design: Fresh CLL cells were isolated and cultured ex vivo with or without stromal co-culture. Molecular and cellular events were studied in PU-H71-treated and control CLL cells. Results: Immunoblotting revealed that a significantly higher amount of HSP90 is present in CLL cells than in peripheral blood mononuclear cells (PBMC), suggesting the chaperone is pathogenically relevant. We found that PU-H71 caused the death of CLL cells in a dose and time dependent manner while the viability of either PBMC or normal B lymphocytes were not affected. PU-H71 induced apoptosis resulting in CLL cell death as it caused mitochondrial cytochrome C release and a decrease in the abundance of several anti-apoptotic proteins. Interestingly, PU-H71 has the ability to counteract the pro-survival effects of the stroma and caused apoptosis in CLL cells co-cultured with stroma. To gain mechanistic insights into how PU-H71 acts, we examined the BCR signaling pathway. We found that the amounts of several key components of the pathway were reduced by PU-H71 treatment. This occurred even in the presence of stromal co-culture. The results suggest that PU-H71 antagonizes the function of HSP90 leading to the destabilization of the BCR signaling transducers. A chemical pull-down experiment revealed the co-existence of the BCR components and HSP90 in the same complex, suggesting these BCR constituents are indeed clients of HSP90 in CLL cells. Further, specific genetic knock-down of the signal transducers by siRNA confirmed their key roles in mediating the survival of CLL cells. Conclusions: PU-H71 antagonizes stroma-induced pro-survival effects in CLL through its inhibition of the B-cell receptor signaling pathway. Our results suggest that PU-H71 may serve as a useful therapy against CLL and is worth further clinical development. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of Bruton's Tyrosine Kinase in B Cell Development

2001 ◽  
Vol 8 (3-4) ◽  
pp. 171-181 ◽  
Author(s):  
Alex Maas ◽  
Rudolf W. Hendriks
Keyword(s):  
Cell Differentiation ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Mouse Models ◽  
Cell Receptor ◽  
B Cell Development ◽  
B Cell Receptor ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

X-linked agammaglobulinemia (XLA) is one of the most frequent inherited immunodeficiency diseases in man and is characterized by an almost complete arrest of B cell differentiation at the pre-B cell stage. The gene defective in XLA encodes the cytoplasmic signaling molecule Bruton's tyrosine kinase (Btk). Next to the CBA/N strain of mice, carrying a single amino acid substitution mutation in the Btk gene, which results in the X-linked immunodeficiency (xid) phenotype, additional mouse models have been developed to study the role of Btkinvivo. This review discusses the analyses of Btk null-mutants, obtained by gene targeting in embryonic stem cells, and transgenic mice that express wild-type or mutated forms of the Btk gene. These studies provided information on the function of Btk at several important checkpoints throughout B cell development. Analyses of the mouse models indicated that Btk is not essential for pre-B cell receptor signaling in the mouse. By contrast, Btk-mediated B cell receptor signaling appears to be required for the survival of immature B cells in the bone marrow, that have performed a successful immunoglobulin (Ig) L chain locus rearrangement, resultirig in the expression of a non-autoreactive Ig on the membrane. Btk is also shown to be involved in signaling pathways that govern the development of peripheral B cells, including follicular entry, follicular maturation and plasma cell differentiation.

Clinical Activity of Entospletinib (GS-9973), a Selective Syk Inhibitor, in Patients with CLL Previously Treated with an Inhibitor of B-Cell Receptor Pathway Signaling

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1744-1744 ◽  
Author(s):  
Jeff P. Sharman ◽  
Andrei R. Shustov ◽  
Mitchell R. Smith ◽  
Thomas E. Boyd ◽  
Christopher Hagenstad ◽  
...  
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Research Funding ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Clinical Activity ◽  
Bcr Signaling ◽  
B Cell Receptor Signaling ◽  
Previously Treated ◽  
Cell Receptor Signaling

Abstract Background Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR) signaling pathway has been a successful therapeutic strategy for chronic lymphocytic leukemia (CLL), with both ibrutinib, an inhibitor of BTK (BTKi) and idelalisib, an inhibitor of PI3Kdelta (PI3Ki), approved for this indication. Entospletinib activity in CLL was recently reported, and preclinical data suggested that entospletinib may be effective even in the context of resistance to BTK therapy, including that conferred by activation of PLCγ2. (Liu, Blood -2015-02-626846) Methods GS-US-339-0102 is an ongoing phase2 trial of entospletinib in CLL and NHL (NCT01799889). The study protocol was amended to add 40 patients in each of 2 CLL cohorts who have been previously treated with BCR signaling pathway (BTK/PI3K) inhibitors. These patients were treated with entospletinib monotherapy (400mg BID) and evaluated using modified Hallek/IWG-CLL criteria every 2-3 months as previously described in Sharman, Blood 2015:125(5). Results As of July 20, 2015, 8 patients with preceding BCR pathway signaling inhibitor treatment have been enrolled, 5 with preceding BTKi therapy (4 with ibrutinib, 1 with AVL-292) and 3 with preceding PI3Ki therapy (idelalisib). The median duration of preceding BTKi treatment was 51 weeks (range 2-85 weeks) and the median duration of preceding PI3Ki treatment was 106 weeks (range 74-168 weeks). Two patients had progressed on prior BTKi and 2 were intolerant (cause missing for 1 patient), while 2 patients progressed on PI3Ki and 1 was intolerant. All 5 patients with preceding BTKi and 2 out of 3 patients with prior PI3Ki remain on entospletinib treatment. Of the 5 patients who were previously treated with BTKi, the ongoing duration of treatment with entospletinib is 8, 8, 13, 25, and 39 weeks. For the 3 patients with preceding PI3Ki, two patients have ongoing treatment of 18 and 26 weeks; one patient stopped treatment and died after 23 weeks due to a cardiac arrest that is not believed to be related to the study drug. The most common treatment-emergent AEs (N=number; any Grade/≥Gr 3, independent of causality) were decreased appetite (3/0), contusion (2/0), dyspepsia (2/0), fatigue (2/0), dehydration (1/1), cardiac arrest (1/1); common laboratory abnormalities were anemia (5/1), neutropenia (4/1), thrombocytopenia (3/2), increased lipase (1/1). Early responses were seen with entospletinib treatment (3 partial response (PR), 1 stable disease, & 3 patients were too early to evaluate) and 1 PD. PR occurred in 1 BTKi and 2 PI3Ki previously treated patients. One patient with preceding PI3Ki developed progressive disease after 8 weeks. Conclusions Early experience from this trial with ongoing enrollment demonstrates that entospletinib has clinical activity following therapy with either BTKi or PI3Ki. No additional safety signals were seen from earlier studies. Additional investigation of treatment with entospletinib following progression with B-cell receptor signaling pathway inhibitors is warranted. Disclosures Sharman: Celgene Corporation: Consultancy, Research Funding; TG Therapeutics, Inc.: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Calistoga: Honoraria; Janssen: Research Funding. Shustov:Celegene, BMS: Consultancy, Honoraria, Research Funding. Smith:celegene, spectrum, genentech: Honoraria. Boyd:US Oncology: Research Funding; Celgene: Speakers Bureau; Genentech, Inc.: Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; GSK: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. He:Gilead Sciences: Employment. Eng:Gilead: Employment. Hu:gilead: Employment. Reddy:gilead: Employment. Mitra:Gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

In Vivo Inhibition of BCR Activation in High-Risk CLL Patients On Therapy with Bruton's Tyrosine Kinase Inhibitor Ibrutinib: Correlative Studies from an Ongoing Phase 2 Clinical Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 186-186
Author(s):  
Julia Hoellenriegel ◽  
Susan O'Brien ◽  
Michael J. Keating ◽  
William G. Wierda ◽  
Joseph J. Buggy ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Bcr Signaling ◽  
Correlative Studies ◽  
Pre Treatment

Abstract Abstract 186 B cell receptor (BCR) signaling is essential for normal B cell development and plays an important role in several B cell malignancies, including chronic lymphocytic leukemia (CLL). BrutonÕs tyrosine kinase (Btk) transmits B cell receptor (BCR) signaling and can be inhibited by ibrutinib, a selective, covalent Btk inhibitor. Because of highly encouraging results with ibrutinib in high-risk CLL patients in the Phase 1/2 trial, we explored the combination of ibrutinib and rituximab in forty high-risk CLL patients, characterized by the presence of 17p deletion or TP53 mutation (treated or untreated), previously treated patients with 11q deletion, or patients with a short remission duration (< 3 years) after first-line chemo-immunotherapy. Here, we present early correlative studies from this trial, focusing on BCR-related CLL responses (chemokine secretion, viability) and CLL cell migration, based on our recent experience with ibrutinib in preclinical CLL models (Ponader S et al., Blood 119:1182–9, 2012). The aim of this study was to determine if preclinical results of Btk inhibition with ibrutinib can be recapitulated in vivo with specimen from the high-risk population enrolled on this trial. Plasma levels of CLL3 and CCL4 (MIP-1α/β), two chemokines secreted by CLL cells in response to BCR activation, were assessed before, at 14, and at 28 days on treatment with ibrutinib. In 28 analyzed patients, we demonstrate robust, significant reductions in CCL3 and CCL4 plasma concentrations after 14 and 28 days of treatment. As shown in Figure 1, plasma CCL3 levels were reduced from 139.6 (± 40.4) pg/mL before treatment to 6.9 (± 0.9) pg/mL or 6.5 (± 0.7) pg/mL after 14 and 28 days of treatment, respectively. We also evaluated in vitro secretion of CCL3 and CCL4 into supernatants of CLL cells isolated from 12 patients before and during ibrutinib therapy in response to stimulation with anti-IgM. Compared to CLL cells from pre-treatment specimen, CLL cells from patients on Ibrutinib therapy showed reduced levels of CLL3 and CCL4 secretion, and additional treatment with Ibrutinib (0.5 μM – 1μM) led to reduced chemokine levels only in pre-treatment samples, indicating complete Btk target inhibition. We next evaluated the effect of ibrutinib on CLL cell viability after anti-IgM stimulation. In pre-treatment samples, ibrutinib abrogated BCR-triggered CLL cell survival. Surprisingly, CLL cells from ibrutinib-treated patients remained anti-IgM responsive in these viability assays. These Btk-independent pro-survival effects could not be inhibited by in vitro treatment with ibrutinib, indicating that some of the anti-IgM-triggered pro-survival signaling can bypass Btk. Next, we analyzed migration of CLL cells towards the chemokines CXCL12 and CXCL13 in transwell chemotaxis assays. Pre-treatment samples displayed significant higher chemotaxis towards CXCL12 and CXCL13 when compared to CLL samples from patients on therapy with ibrutinib. The mean relative migration of such samples toward CXCL12 or CXCL13 was reduced to 28% (± 5%) or 35% (±15%) of respective CLL cells isolated before ibrutinib therapy (100%), n=6. Collectively, our results demonstrate that Ibrutinib blocks BCR-dependent survival and migration responses in high-risk CLL patients in vivo. They also corroborate the validity and robustness of CCL3 and CCL4 as biomarkers for BCR inhibition in CLL patients. Figure 1 Figure 1. Disclosures: O'Brien: Pharmacyclics: Research support Other. Buggy:Pharmacyclics: Employment, Equity Ownership. Burger:Pharmacyclics: Consultancy, Research Funding.

scholarly journals Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1321
Author(s):  
Stefan F. H. Neys ◽  
Peter Heukels ◽  
Jennifer A. C. van Hulst ◽  
Jasper Rip ◽  
Marlies S. Wijsenbeek ◽  
...  
Keyword(s):  
B Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Cell Receptor ◽  
Surface Expression ◽  
B Cell Receptor ◽  
Bcr Signaling

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton’s tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.

scholarly journals Regulation of B Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

2021 ◽  
Author(s):  
Núria Profitós-Pelejà ◽  
Juliana C Santos ◽  
Ana Marín-Niebla ◽  
Gaël Roué ◽  
Marcelo L Ribeiro
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Lymphoma ◽  
Treatment Options ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Bcr Signaling

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte&rsquo;s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B cell non-Hodgkin lymphomas (B-NHLs). In the last decade, emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma like diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

ZAP-70 enhances B-cell–receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 2032-2039 ◽  
Author(s):  
Stefania Gobessi ◽  
Luca Laurenti ◽  
Pablo G. Longo ◽  
Simona Sica ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Tcr Signaling ◽  
Bcr Signaling

Abstract Expression of ZAP-70 is an important negative prognostic factor in chronic lymphocytic leukemia (CLL). This protein tyrosine kinase is a key mediator of T-cell receptor (TCR) signaling and is structurally homologous to Syk, which plays an analogous role in B-cell receptor (BCR) signaling. Recent studies indicate that ZAP-70 may participate in BCR signaling as well, but the mechanism of action is not completely understood. We have now compared antigen receptor-induced activation of ZAP-70 in B cells and T cells by analyzing phosphorylation of critical regulatory tyrosine residues. We show that BCR-mediated activation of ZAP-70 is very inefficient in CLL and lymphoma B cells and is negligible when compared to activation of Syk. Despite the inefficient catalytic activation, the ability of ZAP-70 to recruit downstream signaling molecules in response to antigen receptor stimulation appeared relatively preserved. Moreover, ectopic expression of ZAP-70 enhanced and prolonged activation of several key mediators of BCR signaling, such as the Syk, ERK, and Akt kinases, and decreased the rate of ligand-mediated BCR internalization. We conclude that the role of ZAP-70 in BCR signaling is quite distinct from its role in TCR signaling and is likely mediated by inhibition of events that terminate the signaling response.

scholarly journals The sequential role of Mst1/mTORC1/STAT1 activity in chemokine receptor 2-regulated B cell receptor signaling

2021 ◽  
Author(s):  
Yingzi Zhu ◽  
Heng Gu ◽  
Lu Yang ◽  
Na Li ◽  
Qiuyue Chen ◽  
...  
Keyword(s):  
Cell Signaling ◽  
B Cell ◽  
Signaling Pathway ◽  
Cell Activation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
B Cell Activation ◽  
B Cell Signaling ◽  
Bcr Signaling

Background: Chemokine (C-C motif) receptor 2 (CCR2) contributes to autoimmune pathogenesis. However, the effect of CCR2 on B cell signaling and its role in autoimmunity remains unclear. Herein, we investigated the role of CCR2 in the B cell receptor (BCR) signaling pathway and aimed to illustrate its potential molecular mechanisms of action. Methods: To investigate the alterations in B cell signaling and the immune response, we used flow cytometry, western blotting, microscopic techniques, Seahorse assay, and immunofluorescence assay on samples from C57BL/6 mice and germinal CCR2-deletion mice. Results: The absence of CCR2 disturbed follicular B cell development. Furthermore, CCR2 absence was correlated with increased mTORC1-mediated energy metabolism and enhanced early B cell activation, which were induced by the up-regulation of BCR proximal signaling and F-actin accumulation. Mst1 and STAT1 were key factors in up-regulating the B cell activation in CCR2 deficient mice. The disrupted peripheral B cell differentiation and enhanced B cell signaling were associated with the inhibition mTORC1, Mst1, and STAT1. Moreover, loss of CCR2 caused a weakened T cell dependent antigen response, resulting in decreased antibody secreting cells and diminished antigen specific IgM levels. Conclusion: CCR2 is involved in the regulation of BCR signaling pathway by sequentially activating signaling pathways dominated by Mst1, mTORC1, and STAT1. Our study suggests that CCR2 might represent a novel therapeutic targeted for autoimmune diseases.

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