TY - JOUR
T1 - B cell receptor isotypes differentially associate with cell signaling, kinetics, and outcome in chronic lymphocytic leukemia
AU - Mazzarello, Andrea N.
AU - Gentner-Göbel, Eva
AU - Dühren-Von Minden, Marcus
AU - Tarasenko, Tatyana N.
AU - Nicolò, Antonella
AU - Ferrer, Gerardo
AU - Vergani, Stefano
AU - Liu, Yun
AU - Bagnara, Davide
AU - Rai, Kanti R.
AU - Burger, Jan A.
AU - McGuire, Peter J.
AU - Maity, Palash C.
AU - Jumaa, Hassan
AU - Chiorazzi, Nicholas
N1 - Funding Information:
We thank Matthew Scharff (Albert Einstein College of Medicine, Bronx, New York, USA) and Franco Fais (University of Genoa) for helpful discussions and critical review of the manuscript; Sophia Yancopoulos for assistance with the manuscript preparation; and Christopher Colon for IFC setup. This work was supported in part by philanthropic contributions from the Karches Foundation, The Marks Foundation, The Nash Family Foundation, and the Jean Walton Fund for Leukemia, Lymphoma, and Myeloma Research. This work was also funded by DFG Collaborative Research Projects SFB1074(A10) and SFB1279(B03), and the European Research Council (ERC) advanced grant 694992 to HJ. EGG was supported by the ERC 694992. PCM is an institutional fellow at the Institute for Immunology, University Hospital Ulm.
Publisher Copyright:
Copyright: © 2022, Mazzarello et al.
PY - 2022/1/18
Y1 - 2022/1/18
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI149308
DO - 10.1172/JCI149308
M3 - Article
C2 - 34813501
AN - SCOPUS:85123515084
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
M1 - 149308
ER -