Rituximab inhibits B-cell receptor signaling

Kheirallah, Samar; Caron, Pierre; Gross, Emilie; Quillet‐Mary, Anne; Bertrand‐Michel, Justine; Fournié, Jean‐Jacques; Laurent, Guy; Bezombes, Christine

doi:10.1182/blood-2009-08-237537

Cited by 62 publications

(63 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our study, formation of CLL cell aggregates by CD19 was only reduced by 25% after using protein tyrosine kinase inhibitors, whereas inhibition of F-actin assembly also resulted in a minor inhibitory effect, which is in agreement with previously published results (30). In contrast, the aggregation was completely abrogated by disruption of the cholesterol-rich plasma membrane rafts.…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies pointed to the possible involvement of CD20 in BCR signaling responses, albeit the in vivo significance of these findings is unclear (30). To further examine the physiological differences between the CD19-R and CD19-N subpopulations, we tested the effects of the anti-CD20 therapeutic Ab rituximab on these cells, both in vitro and in vivo.…”

Section: Cd19-responsive Cll Cells Are Preferentially Eliminated In Vmentioning

confidence: 99%

See 1 more Smart Citation

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Herishanu

Kay

Dezorella

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpopulations reacted to sIgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19–signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow–derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Cd19-responsive Cll Cells Are Preferentially Eliminated In Vmentioning

confidence: 99%

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Herishanu

Kay

Dezorella

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Janas et al [38] have shown that rituximab-induced translocation of CD20 to lipid rafts is crucial for increased intracellular Ca 2+ levels and downstream apoptotic signaling. Also the rituximab binding to CD20 significantly interferes with B-cell receptor (BCR) signaling, resulting in a time-dependent inhibition of the BCR-signaling cascade involving Lyn, Syk, PLCc2, Akt, and ERK, and calcium mobilization [39]. Walsh et al [40] have suggested that after the ligation of CD20 by rituximab, CD20 molecules cluster together and associate with the BCR, as shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Imaging and measuring the rituximab-induced changes of mechanical properties in B-lymphoma cells using atomic force microscopy

Liu

et al. 2011

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

“…The integrity of lipid rafts and their association with CD20 and consequent activation of src kinases are all dependent on cholesterol, with cholesterol depletion inhibiting rituximab-induced apoptosis (14). In follicular lymphoma (FL) cell lines, we found that rituximab inhibits B-cell-receptor signaling by preventing B-cell-receptor relocalization into rafts and decreasing raftassociated cholesterol content (15). CD20 translocation into rafts seems to be necessary for calcium mobilization and for rituximab-induced apoptosis in Burkitt lymphoma cell lines (16).…”

Section: Effects Of Rituximab On Lipids and Raftsmentioning

confidence: 92%

Direct Effect of Rituximab in B-Cell–Derived Lymphoid Neoplasias: Mechanism, Regulation, and Perspectives

Bezombes

Fournié

Laurent

2011

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

The anti-CD20 monoclonal antibody rituximab is the backbone of treatment for the B-cell malignancies nonHodgkin lymphoma and chronic lymphocytic leukemia. However, there is a wide variability in response to rituximab treatment, and some patients are refractory to current standard therapies. Rituximab kills B cells by multiple mechanisms of action, including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which are immune-mediated mechanisms, as well as by direct effects on cell signaling pathways and cell membranes following CD20 binding. A large number of events that are affected by rituximab binding have been identified, including lipid raft modifications, kinase and caspase activation, and effects on transcription factors and apoptotic/antiapoptotic molecules. Studies on cell lines and isolated tumor cells have

show abstract

Rituximab inhibits B-cell receptor signaling

Abstract: Rituximab (RTX),

Cited by 62 publications

References 44 publications

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

Imaging and measuring the rituximab-induced changes of mechanical properties in B-lymphoma cells using atomic force microscopy

Direct Effect of Rituximab in B-Cell–Derived Lymphoid Neoplasias: Mechanism, Regulation, and Perspectives

Contact Info

Product

Resources

About