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 6

Ibrutinib treatment downregulates metabolic activities associated with membrane IgM levels and in vivo CLL birth rate.

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Ibrutinib treatment downregulates metabolic activities associated with m...
(A) Mitochondrial respiration parameters calculated based on OCR from mitochondrial stress assay comparing CLL BR Int (n = 5; BR = 0.35%–0.65%) and High (n = 4; BR = 0.80%–1.42%) before (Pre-T) and during in vivo ibrutinib (iBTK) treatment. (B) Glycolytic parameters calculated based on extracellular acidification rate (ECAR) from glycolytic stress assay comparing CLL cases with Int (n = 5; BR = 0.35%–0.65%) and High (n = 4; BR = 0.80%–1.42%) BRs before (Pre-T) and during in vivo ibrutinib (iBTK) therapy. Bars represent mean ± SEM. Each dot represents the average value of 4 or more replicates for a single patient. (C) Changes in metabolic profiles during iBTK treatment. Each dot represents the average OCR and ECAR values for all patients within the BR group ± SEM. Baseline phenotype = basal respiration (OCR) versus glycolysis (ECAR); stressed phenotype = maximal respiration (OCR) versus glycolytic capacity (ECAR). Before (squares) and during treatment (circles) changes are shown for baseline phenotype (red) and stressed phenotype (blue) for CLL clones with Int BR (0.35%–0.65%, left) and High BRs (0.80%–1.42%, right). OCR and ECAR were normalized, defining 0% as the raw value of 0 and 100% as the last raw value of each data set (or first, whichever was larger) and are presented as fractions. For statistical analysis, 1-way ANOVA with Tukey’s test was applied.