B cell receptor isotypes differentially associate with cell signaling, kinetics, and outcome in chronic lymphocytic leukemia
Andrea N. Mazzarello, … , Hassan Jumaa, Nicholas Chiorazzi
Andrea N. Mazzarello, … , Hassan Jumaa, Nicholas Chiorazzi
Published November 23, 2021
Citation Information: J Clin Invest. 2022;132(2):e149308. https://doi.org/10.1172/JCI149308.
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B cell receptor isotypes differentially associate with cell signaling, kinetics, and outcome in chronic lymphocytic leukemia

Abstract

In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events. Since both IgM and IgD carry the same antigen-binding domains, the divergent actions of the receptors are attributed to differences in immunoglobulin (Ig) structure or the outcome of signal transduction. We showed that IgM, not IgD, level and organization associated with CLL-cell birth rate and the type and consequences of BCR signaling in humans and mice. The latter IgM-driven effects were abrogated when BCR signaling was inhibited. Collectively, these studies demonstrated a critical, selective role for IgM in BCR signaling and B cell fate decisions, possibly opening new avenues for CLL therapy.

Authors

Andrea N. Mazzarello, Eva Gentner-Göbel, Marcus Dühren-von Minden, Tatyana N. Tarasenko, Antonella Nicolò, Gerardo Ferrer, Stefano Vergani, Yun Liu, Davide Bagnara, Kanti R. Rai, Jan A. Burger, Peter J. McGuire, Palash C. Maity, Hassan Jumaa, Nicholas Chiorazzi

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Figure 5

Ibrutinib treatment affects both autonomous and surrogate antigen–induced BCR signaling, thereby reducing MCS.

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Ibrutinib treatment affects both autonomous and surrogate antigen–induce...
(A) Representative Ca++ influx analyses of TKO cells expressing IgM CLL–derived BCRs pretreated with ibrutinib (iBTK, right) and solvent (DMSO, left) for autonomous signaling upon stimulation with 4-OHT. (B) Ca++ influx analyses of TKO cells expressing IgM CLL–derived BCRs pretreated with ibrutinib (iBTK, right) and solvent (DMSO, left) for ligand-dependent signaling using anti-light chain (anti-LC) (top) and anti-heavy chain (anti-HC) (bottom) mAbs upon stimulation with 4-OHT. Addition of the stimulus is indicated by black arrows. Three or more experiments were performed for each CLL BCR (n = 4) for autonomous and ligand-dependent signaling in the absence or presence of ibrutinib. (C) Median cell size (MCS) before (Pre-T) and during ibrutinib (iBTK) treatment. Each dot represents the median value of an individual patient. (D) Distribution of single-cell areas for CLL1820 (BR = 0.54% daily) before (Pre-T, orange) and during (light blue) ibrutinib treatment, and for CLL1803 (BR = 1.42% daily) before (Pre-T, yellow) and during (dark blue) treatment. The Mann-Whitney test was used for these statistical analyses.