Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells

2020 ◽  
Author(s):  
Chiara Cavallini ◽  
Marilisa Galasso ◽  
Elisa Dalla Pozza ◽  
Roberto Chignola ◽  
Ornella Lovato ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukaemia ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Receptor Signalling ◽  
Cd20 Antibodies

scholarly journals Pro-apoptotic TP53 homolog TAp63 is repressed via epigenetic silencing and B-cell receptor signalling in chronic lymphocytic leukaemia

2013 ◽  
Vol 163 (5) ◽  
pp. 590-602 ◽  
Author(s):  
Leigh A. Humphries ◽  
J. Claire Godbersen ◽  
Olga V. Danilova ◽  
Prabhjot Kaur ◽  
Brock C. Christensen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Lymphocytic Leukaemia ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Epigenetic Silencing ◽  
Receptor Signalling

Characterisation of B Cell Receptor-Induced NF-KB Activation In Chronic Lymphocytic Leukaemia Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 375-375 ◽  
Author(s):  
Fatima Talab ◽  
Victoria Thompson ◽  
John C Allen ◽  
Ke Lin ◽  
Joseph R Slupsky
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Cell Cultures ◽  
Lymphocytic Leukaemia ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Nfkb Pathway

Abstract Abstract 375 B cell receptor (BCR) signaling promotes survival of the malignant clone in chronic lymphocytic leukaemia (CLL) through its ability to stimulate NFkB pathway signaling. In lymphoid cells, antigen receptor stimulation of this pathway is achieved by engaging the Carma-1 – Bcl10 – MALT1 (CBM) complex for eventual activation of I-kB kinases (IKKs). In B cells, protein kinase C beta (PKCbeta) is an important mediator of CBM complex activation. However, in CLL cells we found that PKCs do not appear to have a role in BCR-mediated NFkB pathway signaling, despite high expression levels of PKCbeta, because the presence of specific inhibitors of this kinase (LY379196 and bisindolylmaleimide-I) has no effect on the induction of IKK phosphorylation during BCR crosslinking. Examination of CBM complex expression suggests an explanation for this phenomenon; the expression levels of Carma-1 and MALT-1 are largely similar in CLL and normal B cells, but the expression of Bcl10 is much reduced in CLL cells. These findings, taken together with the established role of Bcl10 in the pathway of BCR-induced NFkB activation, suggest that CLL cells may employ a different mechanism to activate this pathway during BCR stimulation. Tyrosine kinases are known to play a role in BCR-induced IKK activation in CLL cells because compounds like dasatinib and PP2 inhibit NFkB pathway activation by BCR. One possible tyrosine kinase is c-Abl because we have shown this protein to be overexpressed in CLL cells, where it plays a role in activation of the NFkB pathway. To investigate the role of c-Abl in BCR-induced IKK activation, we used the inhibitor imatinib and found that the presence of this compound partially inhibited IKK phosphorylation in BCR-stimulated CLL cells. However, imatinib can also inhibit Lck, a T cell-specific src-family tyrosine kinase that is expressed by CLL cells. To differentiate between Lck- and c-Abl-mediated BCR signals we used the specific inhibitor 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2d] pyrimidin-7-yl-cyclopentane (Lck-i). We found that the presence of this compound in CLL cell cultures undergoing BCR stimulation almost completely inhibited the induction of IKK activation. Investigation of Lck-i specificity revealed this compound did not inhibit either c-Abl or Lyn at the concentration used to inhibit Lck in CLL cell cultures. Further investigation of the effects of Lck-i showed that this compound was also effective in inhibiting BCR-induced activation of the Akt and ERK signaling pathways. Taken together, these data suggest a major role for Lck in BCR-mediated signaling in CLL cells, and question the existing paradigm on the importance of Lyn. Disclosures: No relevant conflicts of interest to declare.

B-cell receptor stereotypy and chronic lymphocytic leukaemia

2014 ◽  
Vol 1 (2) ◽  
pp. e52-e53
Author(s):  
Anne-Sophie Michallet ◽  
Bertrand Coiffier
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Lymphocytic Leukaemia ◽  
Cell Receptor ◽  
B Cell Receptor

scholarly journals Defective assembly of the B-cell receptor chains accounts for its low expression in B-chronic lymphocytic leukaemia

2002 ◽  
Vol 118 (4) ◽  
pp. 976-985 ◽  
Author(s):  
Béatrice Payelle-Brogard ◽  
Christian Magnac ◽  
Andres Alcover ◽  
Pascal Roux ◽  
Guillaume Dighiero
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Lymphocytic Leukaemia ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Low Expression

scholarly journals Does B Cell Receptor Signaling in Chronic Lymphocytic Leukaemia Cells Differ from That in Other B Cell Types?

Scientifica ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Joseph R. Slupsky
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Lymphocytic Leukaemia ◽  
Signal Transduction Pathway ◽  
Cell Types ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Incurable Disease ◽  
B Cell Receptor Signaling

Chronic lymphocytic leukaemia (CLL) is an incurable malignancy of mature B cells. CLL is important clinically in Western countries because of its commonality and because of the significant morbidity and mortality associated with the progressive form of this incurable disease. The B cell receptor (BCR) expressed on the malignant cells in CLL contributes to disease pathogenesis by providing signals for survival and proliferation, and the signal transduction pathway initiated by engagement of this receptor is now the target of several therapeutic strategies. The purpose of this review is to outline current understanding of the BCR signal cascade in normal B cells and then question whether this understanding applies to CLL cells. In particular, this review studies the phenomenon of anergy in CLL cells, and whether certain adaptations allow the cells to overcome anergy and allow full BCR signaling to take place. Finally, this review analyzes how BCR signals can be therapeutically targeted for the treatment of CLL.

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