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

J Immunol. 2016 May 15;196(10):4410-7. doi: 10.4049/jimmunol.1502297. Epub 2016 Apr 8.


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.

MeSH terms

  • B-Lymphocytes / immunology*
  • Clonal Anergy*
  • Gene Expression
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Variable Region / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • MAP Kinase Signaling System
  • MicroRNAs / genetics*
  • Receptors, Antigen, B-Cell / immunology*
  • Toll-Like Receptor 2 / genetics*
  • Toll-Like Receptors / genetics*


  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • MIR17HG, human
  • MicroRNAs
  • Receptors, Antigen, B-Cell
  • TLR11 protein, human
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptors