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 NtoufaNikos PapakonstantinouBenedetta ApollonioMaria GounariChrysi GaligalidouEleonora FonteAchilles AnagnostopoulosChrysoula BelessiMarta MuzioPaolo GhiaKostas StamatopoulosPublished in: Journal of immunology (Baltimore, Md. : 1950) (2016)
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.
Keyphrases
- chronic lymphocytic leukemia
- acute lymphoblastic leukemia
- chronic myeloid leukemia
- tyrosine kinase
- cell proliferation
- signaling pathway
- long non coding rna
- toll like receptor
- immune response
- induced apoptosis
- long noncoding rna
- pi k akt
- end stage renal disease
- ejection fraction
- newly diagnosed
- prognostic factors
- chronic kidney disease
- nuclear factor
- reactive oxygen species
- oxidative stress
- epithelial mesenchymal transition
- patient reported outcomes
- peritoneal dialysis
- patient reported