Functional differences between IgM and IgD signaling in chronic lymphocytic leukemia

Elisa Ten Hacken, Mariela Sivina, Ekaterina Kim, Susan O'Brien, William G. Wierda, Alessandra Ferrajoli, Zeev Estrov, Michael J. Keating, Thomas Oellerich, Cristina Scielzo, Paolo Ghia, Federico Caligaris-Cappio, Jan A. Burger

Research output: Contribution to journalArticlepeer-review

Abstract

The online version of this article contains supplemental material. BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined.We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3. In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.

Original languageEnglish
Pages (from-to)2522-2531
Number of pages10
JournalJournal of Immunology
Volume197
Issue number6
DOIs
Publication statusPublished - Sep 15 2016

ASJC Scopus subject areas

  • Immunology

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