scholarly journals NOVEL AGENTS AND EMERGING STRATEGIES FOR TARGETING THE B-CELL RECEPTOR PATHWAY IN CLL

2012 ◽  
Vol 4 (1) ◽  
pp. e2012067 ◽  
Author(s):  
Dimitar Efremov ◽  
Adrian Wiestner ◽  
Luca Laurenti
Keyword(s):  
B Cell ◽  
Leukemic Cell ◽  
Cell Receptor ◽  
Therapeutic Agents ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Receptors ◽  
Clinical Responses ◽  
Preclinical And Clinical Studies ◽  
Marked Dependence

Chronic lymphocytic leukemia (CLL) is a disease of malignant CD5+ B lymphocytes that are characterized by frequent expression of autoreactive B-cell receptors (BCRs) and marked dependence on microenvironmental signals for proliferation and survival. Among the latter, signals propagated through the BCR are believed to play a key role in leukemia initiation, maintenance and evolution. Drugs that can disrupt these signals have recently emerged as potential therapeutic agents in CLL and several of them are currently being evaluated in clinical trials. Particularly promising clinical responses have been obtained with inhibitors of the kinases SYK, BTK, and PI3Kδ, which function by blocking BCR signal transduction. In addition, recent studies focusing on the phosphatase PTPN22, which is involved in the pathogenesis of multiple autoimmune diseases and is markedly overexpressed in CLL cells, suggest that it may be possible in the future to develop strategies that will selectively reprogram BCR survival signals into signals that induce leukemic cell death. This review focuses on the biological basis behind these strategies and highlights some of the most promising BCR-targeting agents in ongoing preclinical and clinical studies.  

scholarly journals Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors

2020 ◽  
Vol 1 (3) ◽  
pp. 131-152 ◽  
Author(s):  
Rachael Arthur ◽  
Beatriz Beatriz Valle-Argos ◽  
Andrew J. Steele ◽  
Graham Packham
Keyword(s):  
B Cell ◽  
Kinase Inhibitors ◽  
Early Stage ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Responses ◽  
B Cell Receptor Signaling ◽  
Btk Inhibitor ◽  
Emergence Of Resistance

Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell receptor signaling and the irreversible BTK inhibitor ibrutinib can trigger dramatic clinical responses in treated patients. However, emergence of resistance and toxicity are major limitations which lead to treatment discontinuation. There remains, therefore, a clear need for new therapeutic options. In this review, we discuss recent progress in the development of BTK-targeted proteolysis targeting chimeras (PROTACs) describing how such agents may provide advantages over ibrutinib and highlighting features of PROTACs that are important for the development of effective BTK degrading agents. Overall, PROTACs appear to be an exciting new approach to target BTK. However, development is at a very early stage and considerable progress is required to refine these agents and optimize their drug-like properties before progression to clinical testing.

The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 846-855 ◽  
Author(s):  
Pablo G. Longo ◽  
Luca Laurenti ◽  
Stefania Gobessi ◽  
Simona Sica ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Viability ◽  
B Cell ◽  
Cell Survival ◽  
Leukemic Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Antiapoptotic Proteins

Sustained engagement of the B-cell receptor (BCR) increases apoptosis resistance in chronic lymphocytic leukemia (CLL) B cells, whereas transient stimulation usually has an opposite effect. The antiapoptotic BCR signal has been associated with prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the relative contribution of the Akt and ERK kinases in regulating CLL B-cell survival, we introduced constitutively active mutants of Akt and MEK in primary CLL B cells and evaluated changes in the expression of relevant pro- and antiapoptotic proteins. Sustained activation of Akt resulted in increased leukemic cell viability and increased expression of the antiapoptotic proteins Mcl-1, Bcl-xL, and X-linked inhibitor of apoptosis protein (XIAP), thus largely recapitulating the effects of sustained BCR stimulation. Constitutively active MEK2 also up-regulated XIAP, but did not show a significant impact on leukemic cell survival. Down-regulation of Mcl-1 by siRNA treatment induced rapid and potent apoptosis in CLL B cells and blocked the antiapoptotic effect of sustained BCR stimulation, whereas down-regulation of Bcl-xL and XIAP did not affect leukemic cell viability. These data demonstrate that Akt and Mcl-1 are major components of a survival pathway that can be activated in CLL B cells by antigen stimulation.

scholarly journals Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

2021 ◽  
Author(s):  
Sarah Wilmore ◽  
Karly-Rai Rogers-Broadway ◽  
Joe Taylor ◽  
Elizabeth Lemm ◽  
Rachel Fell ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mrna Translation ◽  
Cell Receptor ◽  
Memory B Cells ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Mrna Stabilization

AbstractSignaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

scholarly journals Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia

Haematologica ◽  
2014 ◽  
Vol 99 (11) ◽  
pp. 1722-1730 ◽  
Author(s):  
A.-C. Bergh ◽  
C. Evaldsson ◽  
L. B. Pedersen ◽  
C. Geisler ◽  
K. Stamatopoulos ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Receptor Response

scholarly journals Role of NFAT in Chronic Lymphocytic Leukemia and Other B-Cell Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Ilenia Sana ◽  
Maria Elena Mantione ◽  
Piera Angelillo ◽  
Marta Muzio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Distinct Pattern ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Activated T Cells ◽  
Inflammatory Microenvironment

In recent years significant progress has been made in the clinical management of chronic lymphocytic leukemia (CLL) as well as other B-cell malignancies; targeting proximal B-cell receptor signaling molecules such as Bruton Tyrosine Kinase (BTK) and Phosphoinositide 3-kinase (PI3Kδ) has emerged as a successful treatment strategy. Unfortunately, a proportion of patients are still not cured with available therapeutic options, thus efforts devoted to studying and identifying new potential druggable targets are warranted. B-cell receptor stimulation triggers a complex cascade of signaling events that eventually drives the activation of downstream transcription factors including Nuclear Factor of Activated T cells (NFAT). In this review, we summarize the literature on the expression and function of NFAT family members in CLL where NFAT is not only overexpressed but also constitutively activated; NFAT controls B-cell anergy and targeting this molecule using specific inhibitors impacts on CLL cell viability. Next, we extend our analysis on other mature B-cell lymphomas where a distinct pattern of expression and activation of NFAT is reported. We discuss the therapeutic potential of strategies aimed at targeting NFAT in B-cell malignancies not overlooking the fact that NFAT may play additional roles regulating the inflammatory microenvironment.

scholarly journals B-cell receptor stereotyped subsets and outcome for patients with chronic lymphocytic leukemia in the HOVON 68 trial

2021 ◽  
Author(s):  
Fie J. Vojdeman ◽  
Lone B. Pedersen ◽  
Doreen te Raa ◽  
Vesa Juvonen ◽  
Yvette van Norden ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia

scholarly journals Constitutive Activation of the B Cell Receptor Underlies Dysfunctional Signaling in Chronic Lymphocytic Leukemia

Cell Reports ◽  
2019 ◽  
Vol 28 (4) ◽  
pp. 923-937.e3 ◽  
Author(s):  
Carly G.K. Ziegler ◽  
Joel Kim ◽  
Kelly Piersanti ◽  
Alon Oyler-Yaniv ◽  
Kimon V. Argyropoulos ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Constitutive Activation

scholarly journals Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia

Blood ◽  
2013 ◽  
Vol 121 (24) ◽  
pp. 4902-4905 ◽  
Author(s):  
Davide Rossi ◽  
Valeria Spina ◽  
Riccardo Bomben ◽  
Silvia Rasi ◽  
Michele Dal-Bo ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Key Points ◽  
Genetic Profiles

Key Points BCR subsets 2 and 8 show specific genetic profiles influencing CLL course.

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