B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.

• MeSH
• Adenine analogs & derivatives   pharmacology   MeSH
• CD40 Antigens genetics   metabolism   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   genetics   metabolism   pathology   MeSH
• Adult MeSH
• TNF Receptor-Associated Factor 4 genetics   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• MicroRNAs genetics   MeSH
• Survival Rate MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Tumor Cells, Cultured MeSH
• Follow-Up Studies MeSH
• Piperidines pharmacology   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins c-bcr antagonists & inhibitors   MeSH
• Proto-Oncogene Proteins c-myc genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenine MeSH
• CD40 Antigens MeSH
• BCR protein, human MeSH Browser
• TNF Receptor-Associated Factor 4 MeSH
• ibrutinib MeSH Browser
• MicroRNAs MeSH
• MIRN29a microRNA, human MeSH Browser
• MYC protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Piperidines MeSH
• Proto-Oncogene Proteins c-bcr MeSH
• Proto-Oncogene Proteins c-myc MeSH
• TRAF4 protein, human MeSH Browser

MicroRNAs (miRNAs) represent important regulators of gene expression besides transcriptional control. miRNA regulation can be involved in the cell developmental fate decisions, but can also have more subtle roles in buffering stochastic fluctuations in gene expression. They participate in pathways fundamental to B-cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches, and the production and class-switching of immunoglobulins. miRNAs influence B-cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. In this review, we discuss miRNAs with essential functions in malignant B-cell development (such as miR-150, miR-155, miR-21, miR-34a, miR-17-92 and miR-15-16). We also put these miRNAs in the context of normal B-cell differentiation, as this is intimately connected to neoplastic B-cell development. We review miRNAs' role in the most common B-cell malignancies, including chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). We focus on miR-contribution to the regulation of important signalling pathways (such as NF-κB, PI3K/AKT and TGF-β), BCR signalling and its modulators (such as PTEN, SHIP-1, ZAP-70, GAB1 and BTK), anti- and pro-apoptotic proteins (such as BCL2, MCL1, TCL1, BIM, p53 and SIRT1) and transcription factors (such as MYC, MYB, PU.1, FOXP1 and BCL6). We also discuss the association of miRNAs' expression levels with the patients' survival and response to therapy, summarizing their potential use as predictive and prognostic markers. Importantly, the targeting of miRNAs (like use of anti-miR-155 or miR-34a mimic) could provide a novel therapeutic approach as evidenced by tumour regression in xenograft mouse models and initial promising data from clinical trials.

• MeSH
• Apoptosis MeSH
• Lymphoma, B-Cell genetics   metabolism   MeSH
• Gene Deletion MeSH
• Humans MeSH
• MicroRNAs metabolism   MeSH
• Mice MeSH
• NF-kappa B p50 Subunit metabolism   MeSH
• DNA Damage MeSH
• Receptors, Antigen, B-Cell metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Signal Transduction MeSH
• Gene Expression Profiling MeSH
• Neoplasm Transplantation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• MicroRNAs MeSH
• MIRN150 microRNA, human MeSH Browser
• MIRN155 microRNA, human MeSH Browser
• MIRN21 microRNA, human MeSH Browser
• MIRN34 microRNA, human MeSH Browser
• NF-kappa B p50 Subunit MeSH
• NFKB1 protein, human MeSH Browser
• Receptors, Antigen, B-Cell MeSH

High-level leukemia cell expression of micro-RNA 155 (miR-155) is associated with more aggressive disease in patients with chronic lymphocytic leukemia (CLL), including those cases with a low-level expression of ζ-chain-associated protein of 70 kD. CLL with high-level miR-155 expressed lower levels of Src homology-2 domain-containing inositol 5-phosphatase 1 and were more responsive to B-cell receptor (BCR) ligation than CLL with low-level miR-155. Transfection with miR-155 enhanced responsiveness to BCR ligation, whereas transfection with a miR-155 inhibitor had the opposite effect. CLL in lymphoid tissue expressed higher levels of miR155HG than CLL in the blood of the same patient. Also, isolated CD5(bright)CXCR4(dim) cells, representing CLL that had been newly released from the microenvironment, expressed higher levels of miR-155 and were more responsive to BCR ligation than isolated CD5(dim)CXCR4(bright) cells of the same patient. Treatment of CLL or normal B cells with CD40-ligand or B-cell-activating factor upregulated miR-155 and enhanced sensitivity to BCR ligation, effects that could be blocked by inhibitors to miR-155. This study demonstrates that the sensitivity to BCR ligation can be enhanced by high-level expression of miR-155, which in turn can be induced by crosstalk within the tissue microenvironment, potentially contributing to its association with adverse clinical outcome in patients with CLL.

• MeSH
• CD5 Antigens genetics   metabolism   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   mortality   pathology   MeSH
• Adult MeSH
• Phosphoric Monoester Hydrolases genetics   metabolism   MeSH
• Inositol Polyphosphate 5-Phosphatases MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Middle Aged MeSH
• Humans MeSH
• CD40 Ligand genetics   metabolism   MeSH
• RNA, Messenger genetics   MeSH
• MicroRNAs genetics   MeSH
• Survival Rate MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Tumor Microenvironment MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Prognosis MeSH
• ZAP-70 Protein-Tyrosine Kinase genetics   metabolism   MeSH
• Flow Cytometry MeSH
• Receptors, Antigen, B-Cell genetics   metabolism   MeSH
• Receptors, CXCR4 genetics   metabolism   MeSH
• Gene Expression Regulation, Leukemic * MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Signal Transduction MeSH
• Calcium metabolism   MeSH
• Blotting, Western MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• CD5 Antigens MeSH
• Phosphoric Monoester Hydrolases MeSH
• Inositol Polyphosphate 5-Phosphatases MeSH
• CD40 Ligand MeSH
• RNA, Messenger MeSH
• MicroRNAs MeSH
• MIRN155 microRNA, human MeSH Browser
• Biomarkers, Tumor MeSH
• ZAP-70 Protein-Tyrosine Kinase MeSH
• Receptors, Antigen, B-Cell MeSH
• Receptors, CXCR4 MeSH
• Calcium MeSH
• ZAP70 protein, human MeSH Browser

We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome.

• MeSH
• Adaptor Proteins, Signal Transducing biosynthesis   genetics   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   metabolism   MeSH
• Adult MeSH
• Forkhead Transcription Factors biosynthesis   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• RNA, Small Interfering MeSH
• MicroRNAs genetics   MeSH
• Receptors, Antigen, B-Cell genetics   metabolism   MeSH
• Gene Expression Regulation, Leukemic genetics   MeSH
• Repressor Proteins biosynthesis   genetics   MeSH
• Oligonucleotide Array Sequence Analysis MeSH
• Aged MeSH
• Signal Transduction * physiology   MeSH
• Transfection MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• Forkhead Transcription Factors MeSH
• FOXP1 protein, human MeSH Browser
• GAB1 protein, human MeSH Browser
• RNA, Small Interfering MeSH
• MicroRNAs MeSH
• MIRN150 microRNA, human MeSH Browser
• Receptors, Antigen, B-Cell MeSH
• Repressor Proteins MeSH