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B Cell Anergy Modulated by TLR1/2 and the miR-17 similar to 92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4
Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece.;George Papanikolaou Hosp, Dept Hematol, Thessaloniki 57010, Greece.;George Papanikolaou Hosp, Hematopoiet Cell Transplantat Unit, Thessaloniki 57010, Greece..
Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece.;George Papanikolaou Hosp, Dept Hematol, Thessaloniki 57010, Greece.;George Papanikolaou Hosp, Hematopoiet Cell Transplantat Unit, Thessaloniki 57010, Greece..
IRCCS San Raffaele Sci Inst, Div Expt Oncol, I-20132 Milan, Italy..
IRCCS San Raffaele Sci Inst, Div Expt Oncol, I-20132 Milan, Italy..
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2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 10, 4410-4417 p.Article in journal (Refereed) PublishedText
Abstract [en]

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 miR17 similar to 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 similar to 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.

Place, publisher, year, edition, pages
2016. Vol. 196, no 10, 4410-4417 p.
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-297784DOI: 10.4049/jimmunol.1502297ISI: 000375831200043PubMedID: 27059597OAI: oai:DiVA.org:uu-297784DiVA: diva2:943617
Funder
EU, European Research Council
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2016-06-28Bibliographically approved

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