scholarly journals Comparison of the mRNA expression profile of B-cell receptor components in normal CD5-high B-lymphocytes and chronic lymphocytic leukemia: a key role of ZAP70

2017 ◽  
Vol 6 (12) ◽  
pp. 2984-2997 ◽  
Author(s):  
Aleena A. Gladkikh ◽  
Daria M. Potashnikova ◽  
Victor Tatarskiy ◽  
Margarita Yastrebova ◽  
Alvina Khamidullina ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mrna Expression ◽  
B Lymphocytes ◽  
Expression Profile ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mrna Expression Profile

CLL Biology and Prognosis

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 278-284 ◽  
Author(s):  
Guillaume Dighiero
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocyte ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Staging Systems ◽  
Cellular Markers ◽  
Major Progress

Abstract Chronic lymphocytic leukemia (CLL) follows an extremely variable course with survival ranging from months to decades. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in CLL patients. In particular, the mutational profile of Ig genes and some cytogenetic abnormalities have been found to be important predictors of prognosis in CLL. However, this progress has raised new questions about the biology and prognosis of the disease, some of which are addressed here. Such questions include: 1) What is the role of the B-cell receptor (BCR) in CLL pathogenesis? 2) Is CLL one disease? 3) Is CLL an accumulative disease? 4) What is the normal counterpart of the CLL B lymphocyte? 5) Have the Rai and Binet staging systems become obsolete? 6) Which is the best surrogate for Ig mutational profiles?

Leukemic B Cells from Patients with Chronic Lymphocytic Leukemia Show Anomalous Lyn Tyrosine Kinase which Contributes to Defective Apoptosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1917-1917
Author(s):  
Livio Trentin ◽  
Anna Maria Brunati ◽  
Antonella Contri ◽  
Anna Cabrelle ◽  
Marta Miorin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Cyclosporin A ◽  
B Cell ◽  
B Lymphocytes ◽  
Protein Level ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of mature B lymphocytes in the G0/G1 phase of the cell cycle, expressing B-cell related (i.e. CD19, surface immunoglobulins) and unrelated molecules (CD5 and CD23). The signal transduction pathways underlying the abnormalities of these leukemic cells are poorly understood and no data are available on deregulated cell signalling in B-CLL. Since Lyn activation plays a pivotal role in the signaling cascade triggered by BCR engagement, we investigated whether this kinase may be involved in CLL pathogenesis. In this study, we investigated freshly isolated and purified malignant B cells obtained from 40 CLL patients and we observed that the Src-kinase Lyn, the switch molecule coupling B-cell-receptor to downstream signaling, displays anomalous properties. Western blot and confocal analyses demonstrated that Lyn is overexpressed at the protein level in leukemic cells as compared to normal B-lymphocytes with a substantial aliquot of the kinase anomalously present in the cytosol of leukemic cells. While in normal B lymphocytes Lyn activation is triggered by B-cell-receptor engagement with anti-IgM antibodies, in freshly isolated leukemic cells this kinase is constitutively active and accounts for high basal protein tyrosine-phosphorylation and low responsiveness to IgM-ligation. To address the question of whether the upregulation of Lyn protein and activity plays a role in the defective apoptosis of leukemic cells, we investigated the relationship between Lyn and the cell survival of malignant lymphocytes in the presence of either dexamethazone and cyclosporin A, which are known to induce apoptosis of human lymphocytes, or PP2 and SU6656, which are selective inhibitors of Lyn. When leukemic cells were cultured in the presence of cyclosporin A or dexamethazone, a marked increase in apoptosis was observed as compared to cells cultured in medium alone, and this effect correlated with a great decrease in both basal activity and protein level of Lyn. The exposure of the leukemic cells to PP2 and SU6656 caused both the inhibition of the overexpressed Lyn activity and marked cell apoptosis. These findings suggest a direct correlation between high basal Lyn activity and defects in the induction of apoptosis in leukemic cells. They also support a critical role for Lyn in B-CLL pathogenesis and identify this tyrosine kinase as a potential therapeutic target for drugs capable of inducing apoptosis in B-CLL leukemic cells.

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
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