TY - JOUR
T1 - 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
AU - Ntoufa, Stavroula
AU - Papakonstantinou, Nikos
AU - Apollonio, Benedetta
AU - Gounari, Maria
AU - Galigalidou, Chrysi
AU - Fonte, Eleonora
AU - Anagnostopoulos, Achilles
AU - Belessi, Chrysoula
AU - Muzio, Marta
AU - Ghia, Paolo
AU - Stamatopoulos, Kostas
PY - 2016/5/15
Y1 - 2016/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84975061775&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84975061775&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1502297
DO - 10.4049/jimmunol.1502297
M3 - Article
AN - SCOPUS:84975061775
VL - 196
SP - 4410
EP - 4417
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 10
ER -