B cell anergy modulated by TLR1/2 and the MIR-17∼92 cluster underlies the indolent clinical course of chronic lymphocytic leukemia stereotyped subset #4

Stavroula Ntoufa, Nikos Papakonstantinou, Benedetta Apollonio, Maria Gounari, Chrysi Galigalidou, Eleonora Fonte, Achilles Anagnostopoulos, Chrysoula Belessi, Marta Muzio, Paolo Ghia, Kostas Stamatopoulos

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset #4 (mutated IGHV4-34/IGKV2-30 BCR Ig) display a particularly indolent disease course. Immunogenetic studies of the clonotypic BCR Ig of CLL subset #4 suggested a resemblance with B cells rendered anergic through chronic autoantigenic stimulation. In this article, we provide experimental evidence that subset #4 CLL cells show low IgG levels, constitutive ERK1/2 activation, and fail to either release intracellular Ca2+ or activate MAPK signaling after BCR cross-linking, thus displaying a signature of B cell anergy at both biochemical and functional levels. Interestingly, TLR1/2 triggering restored BCR functionality, likely breaching the anergic state, and this was accompanied by induction of the miR-17∼92 cluster, whose members target critical BCR-associated molecules, including MAPKs. In conclusion, we demonstrate BCR anergy in CLL subset #4 and implicate TLR signaling and the miR-17∼92 cluster in the regulation of the anergic state. This detailed signaling profiling of subset #4 has implications for advanced understanding of the complex regulation of intracellular signaling pathways in CLL, currently a major therapeutic target of the disease.

Original languageEnglish
Pages (from-to)4410-4417
Number of pages8
JournalJournal of Immunology
Volume196
Issue number10
DOIs
Publication statusPublished - May 15 2016

ASJC Scopus subject areas

  • Immunology

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