Abstract
Chronic lymphocytic leukemia (CLL) is a disease with variable clinical outcome. Several prognostic factors such as the immunoglobulin heavy chain variable genes (IGHV) mutation status are linked to the B-cell receptor (BCR) complex, supporting a role for triggering the BCR in vivo in the pathogenesis. The miRNA profile upon stimulation and correlation with IGHV mutation status is however unknown. To evaluate the transcriptional response of peripheral blood CLL cells upon BCR stimulation in vitro, miRNA and mRNA expression was measured using hybridization arrays and qPCR. We found both IGHV mutated and unmutated CLL cells to respond with increased expression of MYC and other genes associated with BCR activation, and a phenotype of cell cycle progression. Genome-wide expression studies showed hsa-miR-132-3p/hsa-miR-212 miRNA cluster induction associated with a set of downregulated genes, enriched for genes modulated by BCR activation and amplified by Myc. We conclude that BCR triggering of CLL cells induces a transcriptional response of genes associated with BCR activation, enhanced cell cycle entry and progression and suggest that part of the transcriptional profiles linked to IGHV mutation status observed in isolated peripheral blood are not cell intrinsic but rather secondary to in vivo BCR stimulation.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antibodies, Anti-Idiotypic / pharmacology
-
B-Lymphocytes / drug effects
-
B-Lymphocytes / immunology*
-
B-Lymphocytes / metabolism
-
Cell Cycle / drug effects
-
Cell Cycle / immunology*
-
Cells, Cultured
-
Gene Expression Regulation, Leukemic / drug effects
-
Genome-Wide Association Study
-
Humans
-
Immunoglobulin Heavy Chains / genetics
-
Immunoglobulin Heavy Chains / immunology
-
Immunoglobulin Variable Region / genetics
-
Immunoglobulin Variable Region / immunology
-
Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
-
Leukemia, Lymphocytic, Chronic, B-Cell / immunology
-
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
-
Lymphocyte Activation / drug effects
-
MicroRNAs / genetics*
-
MicroRNAs / immunology
-
Multigene Family
-
Proto-Oncogene Proteins c-myc / genetics*
-
Proto-Oncogene Proteins c-myc / immunology
-
RNA, Messenger / genetics*
-
RNA, Messenger / immunology
-
Receptors, Antigen, B-Cell / agonists*
-
Receptors, Antigen, B-Cell / genetics
-
Receptors, Antigen, B-Cell / immunology
-
Signal Transduction / drug effects
Substances
-
Antibodies, Anti-Idiotypic
-
Immunoglobulin Heavy Chains
-
Immunoglobulin Variable Region
-
MIRN132 microRNA, human
-
MIRN212 microRNA, human
-
MYC protein, human
-
MicroRNAs
-
Proto-Oncogene Proteins c-myc
-
RNA, Messenger
-
Receptors, Antigen, B-Cell
Grants and funding
This work was supported by grants from the Research Foundation – Flanders (FWO) to JP and BV. VP is a Ph. D. fellow of the Agency for Innovation by Science and Technology (IWT); AR and JVe are Ph. D. fellows, PM is a Postdoctoral Fellows and BV is a Senior Clinical Investigator of the FWO. Support: This work was supported by grants from the Research Foundation – Flanders (FWO) to JP and BV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.