title: 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.
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 Ca(2+) 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.
authors.affiliation: Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece; Hematology Department and Hematopoietic Cell Transplantation Unit, George Papanikolaou Hospital, Thessaloniki 57010, Greece;
authors.forename: Stavroula
authors.identifier: 0000-0003-4155-0140
authors.initials: S
authors.lastname: Ntoufa
authors.affiliation: Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece; Hematology Department and Hematopoietic Cell Transplantation Unit, George Papanikolaou Hospital, Thessaloniki 57010, Greece;
authors.forename: Nikos
authors.initials: N
authors.lastname: Papakonstantinou
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;
authors.forename: Benedetta
authors.initials: B
authors.lastname: Apollonio
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;
authors.forename: Maria
authors.initials: M
authors.lastname: Gounari
authors.affiliation: Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece;
authors.forename: Chrysi
authors.initials: C
authors.lastname: Galigalidou
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fonte
authors.affiliation: Hematology Department and Hematopoietic Cell Transplantation Unit, George Papanikolaou Hospital, Thessaloniki 57010, Greece;
authors.forename: Achilles
authors.identifier: 0000-0003-4384-9031
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Hematology Department, Nikea General Hospital, Pireaus 18454, Greece;
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;
authors.forename: Marta
authors.initials: M
authors.lastname: Muzio
authors.affiliation: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; Lymphoma Unit, Department of Onco-Hematology, Università Vita-Salute San Raffaele, Milan 20132, Italy; and.
authors.forename: Paolo
authors.identifier: 0000-0003-3750-7342
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece; Hematology Department and Hematopoietic Cell Transplantation Unit, George Papanikolaou Hospital, Thessaloniki 57010, Greece; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala 75105, Sweden kostas.stamatopoulos@gmail.com.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy; D015870:Gene Expression; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics*; D062085:RNA, Long Noncoding; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D051193:Toll-Like Receptors / Q000235:genetics*
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D011947:Receptors, Antigen, B-Cell; C482902:TLR11 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors