The transcription factor PU.1 (Purine-rich DNA binding, SPI1) is a key regulator of hematopoiesis, whose level is influenced by transcription through its enhancers and its post-transcriptional degradation via microRNA-155 (miR-155). The degree of transcriptional regulation of the PU.1 gene is influenced by repression via DNA methylation, as well as other epigenetic factors, such as those related to progenitor maturation status, which is modulated by the transcription factor Myeloblastosis oncogene (MYB). In this work, we show that combinatorial treatment of acute myeloid leukemia (AML) cells with DNA methylation inhibitors (5-Azacytidine), MYB inhibitors (Celastrol), and anti-miR-155 (AM155) ideally leads to overproduction of PU.1. We also show that PU.1 reactivation can be compensated by miR-155 and that only a combined approach leads to sustained PU.1 derepression, even at the protein level. The triple effect on increasing PU.1 levels in myeloblasts stimulates the myeloid transcriptional program while inhibiting cell survival and proliferation, leading to partial leukemic differentiation.

• Keywords
• 5-Azacytidine, Celastrol, microRNA miR-155, transcription factor PU.1,
• MeSH
• Leukemia, Myeloid, Acute * drug therapy   genetics   MeSH
• Cell Differentiation genetics   MeSH
• Humans MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Proto-Oncogene Proteins genetics   metabolism   MeSH
• Gene Expression Regulation, Leukemic MeSH
• Trans-Activators metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• MicroRNAs * MeSH
• MIRN155 microRNA, human MeSH Browser
• proto-oncogene protein Spi-1 MeSH Browser
• Proto-Oncogene Proteins MeSH
• Trans-Activators MeSH

Primary cutaneous T-cell lymphomas (CTCL) affect the skin and tend to transform and spread. CTCL involves primarily the Mycosis fungoides (MF) and more aggressive Sezary syndrome (SS). Oncogenic microRNAs (miRs) are stable epigenetic inhibitors often deregulated in the tumour and detectable as biomarkers in non-cellular fractions of peripheral blood. The tumour-specific expression of miR-155, miR-203, and miR-205 was shown to correctly diagnose CTCL. We herein asked whether these microRNAs can be used as plasma biomarkers for clinical CTCL monitoring. Patients with CTCL (n = 10) and controls with non-malignant conditions (n = 11) repeatedly donated plasma samples every ca. five months. MicroRNAs were detected in the plasma samples by specifically-primed RT-PCR followed by multivariate analyses of the miR expression dynamics. We herein established the plasma miR-classifier for detecting CTCL based on the miR-155 upregulation and miR-203/miR-205 downregulation with 100% specificity and 94% sensitivity. The 3-miR-score in the consecutive samples coincided with the clinical outcome of MF and SS patients such as the therapy response or changes in the clinical stage or tumor size. Quantitation of the selected microRNAs in plasma is a specific and straightforward approach for evaluating CTCL outcome representing, thus, a valuable tool for CTCL diagnostics and therapy response monitoring.

• Keywords
• Psoriasis vulgaris, Sezary syndrome, atopic dermatitis, cutaneous T-cell lymphomas (CTCL), microRNA, mycosis fungoides,
• MeSH
• Circulating MicroRNA * MeSH
• Lymphoma, T-Cell, Cutaneous blood   diagnosis   genetics   therapy   MeSH
• Skin pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• MicroRNAs genetics   MeSH
• Biomarkers, Tumor * MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Gene Expression Profiling MeSH
• Case-Control Studies MeSH
• Liquid Biopsy MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Circulating MicroRNA * MeSH
• MicroRNAs MeSH
• MIRN155 microRNA, human MeSH Browser
• MIRN203 microRNA, human MeSH Browser
• MIRN205 microRNA, human MeSH Browser
• Biomarkers, Tumor * MeSH

• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell metabolism   mortality   pathology   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• MicroRNAs biosynthesis   MeSH
• Survival Rate MeSH
• Follow-Up Studies MeSH
• Disease-Free Survival MeSH
• RNA, Neoplasm biosynthesis   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• MicroRNAs MeSH
• MIRN150 microRNA, human MeSH Browser
• MIRN155 microRNA, human MeSH Browser
• RNA, Neoplasm MeSH

The transcription factor PU.1 and its inhibitory microRNA-155 (miR-155) are important regulators of B-cell differentiation. PU.1 downregulation coupled with oncogenic miR-155 upregulation has been reported in lymphoid malignancies; however, these data have not been studied across different subtypes in relation to clinical outcomes. We studied expression of miR-155 and PU.1 in the six most prevalent human B-cell lymphomas (n = 131) including aggressive (DLBCL, HL, MCL) and indolent (B-CLL/SLL, MZL, FL) types. Levels of miR-155 and PU.1 inversely correlated in DLBCL, B-CLL/SLL, and FL tumor tissues. In HL tissues, an exceptionally high level of miR-155 was found in patients with unfavorable responses to first-line therapy and those who had shorter survival times. PU.1 downregulation was noted in B-CLL/SLL samples positive for the adverse prognostic markers CD38 and ZAP-70. Upregulation of miR-155 and downregulation of PU.1 expression are integral aspects of lymphoma biology that could mark aggressive behavior of some, but not all, lymphoma types.

• Keywords
• Lymphoma, PU.1, Prognosis, microRNA miR-155,
• MeSH
• ADP-ribosyl Cyclase 1 metabolism   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma metabolism   mortality   MeSH
• MicroRNAs biosynthesis   MeSH
• Biomarkers, Tumor biosynthesis   MeSH
• Prevalence MeSH
• ZAP-70 Protein-Tyrosine Kinase metabolism   MeSH
• Proto-Oncogene Proteins biosynthesis   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• RNA, Neoplasm biosynthesis   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Trans-Activators biosynthesis   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
• Names of Substances
• ADP-ribosyl Cyclase 1 MeSH
• MicroRNAs MeSH
• MIRN155 microRNA, human MeSH Browser
• Biomarkers, Tumor MeSH
• ZAP-70 Protein-Tyrosine Kinase MeSH
• proto-oncogene protein Spi-1 MeSH Browser
• Proto-Oncogene Proteins MeSH
• RNA, Neoplasm MeSH
• Trans-Activators MeSH
• ZAP70 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