BCL6 Programs Lymphoma Cells for Survival and Differentiation through Distinct Biochemical Mechanisms, Both of Which Can Be Therapeutically Targeted.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 225-225 ◽  
Author(s):  
Samir Parekh ◽  
Jose Polo ◽  
Przemyslaw Juszczynski ◽  
Paola Lev ◽  
Stella Ranuncolo ◽  
...  
Keyword(s):  
Cell Death ◽  
Target Genes ◽  
Constitutive Expression ◽  
Lymphoma Cells ◽  
Proliferation And Differentiation ◽  
Different Types ◽  
Biochemical Mechanisms ◽  
Highly Correlated ◽  
On Chip ◽  
Specific Peptide

Abstract The BCL6 transcriptional repressor is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCL). Constitutive expression of BCL6 has been proposed to mediate lymphomagenesis through several mechanisms, including evasion of cell death, proliferation and differentiation blockade. We show here that BCL6 mediates these effects through distinct mechanisms. First, we show that blocking the association of the SMRT corepressor with BCL6 using our specific peptide inhibitor (BPI) abrogates only the survival effects of BCL6 but has no effect on differentiation. Accordingly, BPI upregulates survival genes such as ATR and p53, but not genes associated with differentiation such as Blimp1, XBP and Syndecan. In contrast, BCL6 shRNA upregulates both survival and differentiation genes and induces both cell death and differentiation. We and others have shown that BCL6 can also directly bind to the MTA3 corepressor, which is implicated in differentiation of Burkitt lymphoma cells. We found that BCL6 and MTA3 are co-expressed in DLBCL cells and primary human centroblasts (the precursor cell for most DLBCLs). The endogenous BCL6 and MTA3 proteins interacted in DLBCLs cells in co-immunoprecipitation experiments. In contrast to SMRT blockade with BPI, siRNA depletion of MTA3 induced expression of the Blimp1, XBP and Syndecan but not p53 and ATR. MTA3 depletion induced plasmacytic differentiation within 72 hours as shown in functional assays and by surface markers. We performed ChIP on chip using custom arrays densely tiling with oligonucleotides covering the entire genomic loci of 20 BCL6 target genes. Interestingly, BCL6 formed different types of repression complexes at differentiation genes (Complex with MTA3/NuRD) vs. survival genes (complex with SMRT and N-CoR). BCL6-mediated repression of genes involved in survival and differentiation thus depend on distinct biochemical mechanisms. The relevance of these findings for human disease was underscored by the fact that we found a statistically significant positive correlation between MTA3 and BCL6 gene expression in a database of 176 human DLBCLs (p<0.00001). Likewise, protein expression of BCL6 and MTA3 was also highly correlated (p<0.00001) (74 cases examined) and staining for Blimp1 revealed mutually exclusive expression from MTA3. Taken together these results illustrate the basic mechanisms through which BCL6 mediates DLBCL lymphomagenesis and provide the basis for powerful targeted therapy regimens that could be translated to the clinical setting.

scholarly journals BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2067-2074 ◽  
Author(s):  
Samir Parekh ◽  
Jose M. Polo ◽  
Rita Shaknovich ◽  
Przemyslaw Juszczynski ◽  
Paola Lev ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Chromatin Immunoprecipitation ◽  
Target Gene ◽  
Target Genes ◽  
Constitutive Expression ◽  
Biochemical Mechanisms ◽  
On Chip ◽  
Survival Effect ◽  
Germinal Center B Cells

AbstractThe BCL6 transcriptional repressor is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCLs). Constitutive expression of BCL6 mediates lymphomagenesis through aberrant proliferation, survival, and differentiation blockade. Binding of BCL6 to the SMRT/N-CoR corepressors mediates the BCL6 survival effect in DLBCL. Although the basis for differentiation blockade is unknown in DLBCL, recent data suggest that BCL6 binding to the MTA3 corepressor might be involved. We report that BCL6 and MTA3 are coexpressed in normal germinal center B cells and DLBCL. Depletion of MTA3 in DLBCL cells induced a differentiation-related BCL6 target gene (PRDM1), but not target genes involved in survival. Accordingly, MTA3 and PRDM1 expression are mutually exclusive in germinal center B cells. We performed chromatin immunoprecipitation (ChIP)–on-chip mapping of the PRDM1 locus, identifying a novel BCL6 binding site on intron 3 of the PRDM1 gene, and show that BCL6 recruits MTA3 to this site. In DLBCL cells, MTA3 depletion induced plasmacytic differentiation but did not decrease viability of DLBCL cells. However, MTA3 depletion synergized with a specific BCL6 inhibitor that blocks SMRT/N-CoR binding to decrease DLBCL viability. Taken together, these results show that BCL6 regulates distinct transcriptional programs through the SMRT/N-CoR and MTA3 corepressors, respectively, and provides a basis for combinatorial therapeutic targeting of BCL6.

scholarly journals Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation

2005 ◽  
Vol 168 (7) ◽  
pp. 1065-1076 ◽  
Author(s):  
Alka Mansukhani ◽  
Davide Ambrosetti ◽  
Greg Holmes ◽  
Lizbeth Cornivelli ◽  
Claudio Basilico
Keyword(s):  
Osteoblast Differentiation ◽  
Target Genes ◽  
Expression Profiles ◽  
Constitutive Expression ◽  
Growth Factor Receptor ◽  
Gene Expression Profiles ◽  
Down Regulation ◽  
Activating Mutations ◽  
Proliferation And Differentiation

Activating mutations in fibroblast growth factor receptor 2 (FGFR2) cause several craniosynostosis syndromes by affecting the proliferation and differentiation of osteoblasts, which form the calvarial bones. Osteoblasts respond to FGF with increased proliferation and inhibition of differentiation. We analyzed the gene expression profiles of osteoblasts expressing FGFR2 activating mutations (C342Y or S252W) and found a striking down-regulation of the expression of many Wnt target genes and a concomitant induction of the transcription factor Sox2. Most of these changes could be reproduced by treatment of osteoblasts with exogenous FGF. Wnt signals promote osteoblast function and regulate bone mass. Sox2 is expressed in calvarial osteoblasts in vivo and we show that constitutive expression of Sox2 inhibits osteoblast differentiation and causes down-regulation of the expression of numerous Wnt target genes. Sox2 associates with β-catenin in osteoblasts and can inhibit the activity of a Wnt responsive reporter plasmid through its COOH-terminal domain. Our results indicate that FGF signaling could control many aspects of osteoblast differentiation through induction of Sox2 and regulation of the Wnt–β-catenin pathway.

BCL6 Transcriptionally Reprograms the DLBCL Genome by Forming Distinct Biochemically Active Complexes on Genes Corresponding to Different Pathways.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2646-2646
Author(s):  
Jose M. Polo ◽  
Katerina Chatzi ◽  
Tania Dell’Oso ◽  
Paola Lev ◽  
Ari Melnick
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Chromatin Structure ◽  
Transcriptional Control ◽  
Target Genes ◽  
Biological Effects ◽  
Hematologic Malignancies ◽  
Specific Gene ◽  
Control Mechanisms ◽  
Biochemical Mechanisms

Abstract Aberrant gene expression is a hallmark of cancer, and so it is not surprising that the most common category of oncogenes and tumor suppressors involved in hematologic malignancies are transcription factors. These factors mediate their effects by nucleating biochemically active cofactor complexes to modify the chromatin structure of their respective target genes. BCL6 is a transcriptional repressor and the most commonly involved oncogene in diffuse large B-cell lymphomas. BCL6 represses genes by recruiting several corepressor complexes including SMRT, N-CoR, BCoR; all of which bind to BCL6 through its BTB domain. Each of these complexes has different biochemical functions (e.g. BCoR forms a polycomb complex vs. SMRT which forms an HDAC3 complex). Moreover, our preliminary data suggested that BCL6 uses different sets of corepressors to mediate distinct biological effects, possibly by using different biochemical mechanisms at specific sets of target genes. Therefore, we hypothesized that BCL6 regulates its target genes using different biochemical tools, allowing it to exquisitely fine tune gene expression and provide specific control mechanisms for different biological functions. In order to test this hypothesis we first identified the direct target genes of BCL6 SMRT, N-CoR and BCoR by ChIP-on-chip in DLBCL cells (Ly1 cells) in multiple replicates, and examined whether the overlapping sets of genes corresponded to different gene pathways. We used a 24,000 promoter microarray representing 1.5 KB of sequence for each gene. The results show reproducible binding of BCL6 at 940 promoters, While BCoR bound to 770, SMRT to 545 and N-CoR to 487 promoters respectively. BCL6 and BCoR overlapped at 400 genes, preferentially involved in involve in cell cycle, cell death chromatin structure, ubiquitin dependent process and chemotaxis. BCL6 and SMRT overlapped on 376 genes, involved in immune response, cell motility and also as BCOR cell death, while N-CoR and BCL6 overlapped on 100 genes including transcriptional control and cell death pathways. The overlap between BCoR and SMRT was at 200 genes, BCoR and N-CoR at 60 genes and SMRT and N-CoR at 85 genes. All three overlapped at 50 genes. We also examined whether these corepressors were associated with specific combinations of histone modifications including H3K9 acetylation, H3K9 methylation, H3K4 methylation, H3K27 methylation, H4K16 acetylation and H3K36 acetylation. Taken together, the data indicate that specific subsets of BCL6 target genes are dependent on distinct biochemical mechanisms, suggesting that additional layers of biochemical complexity govern formation of gene repression complexes in DLBCL cells and providing opportunities for highly specific therapeutic targeting of specific gene programs.

scholarly journals Fli-1, an Ets-Related Transcription Factor, Regulates Erythropoietin-Induced Erythroid Proliferation and Differentiation: Evidence for Direct Transcriptional Repression of the Rb Gene during Differentiation

1999 ◽  
Vol 19 (6) ◽  
pp. 4452-4464 ◽  
Author(s):  
Ami Tamir ◽  
Jeff Howard ◽  
Rachel R. Higgins ◽  
You-Jun Li ◽  
Lloyd Berger ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Leukemia Virus ◽  
Constitutive Expression ◽  
Erythroid Differentiation ◽  
Consensus Binding Site ◽  
Erythroid Progenitor ◽  
Proliferation And Differentiation ◽  
Related Transcription Factor

ABSTRACT Erythropoietin (Epo) is a major regulator of erythropoiesis that alters the survival, proliferation, and differentiation of erythroid progenitor cells. The mechanism by which these events are regulated has not yet been determined. Using HB60, a newly established erythroblastic cell line, we show here that Epo-induced terminal erythroid differentiation is associated with a transient downregulation in the expression of the Ets-related transcription factor Fli-1. Constitutive expression of Fli-1 in HB60 cells, similar to retroviral insertional activation of Fli-1 observed in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia, blocks Epo-induced differentiation while promoting Epo-induced proliferation. These results suggest that Fli-1 modulates the response of erythroid cells to Epo. To understand the mechanism by which Fli-1 regulates erythropoiesis, we searched for downstream target genes whose expression is regulated by this transcription factor. Here we show that the retinoblastoma (Rb) gene, which was previously shown to be involved in the development of mature erythrocytes, contains a Fli-1 consensus binding site within its promoter. Fli-1 binds to this cryptic Ets consensus site within the Rb promoter and transcriptionally represses Rb expression. Both the expression level and the phosphorylation status of Rb are consistent with the response of HB60 cells to Epo-induced terminal differentiation. We suggest that the negative regulation ofRb by Fli-1 could be one of the critical determinants in erythroid progenitor cell differentiation that is specifically deregulated during F-MuLV-induced erythroleukemia.

scholarly journals Repression of c-myc Is Necessary but Not Sufficient for Terminal Differentiation of B Lymphocytes In Vitro

2000 ◽  
Vol 20 (23) ◽  
pp. 8684-8695 ◽  
Author(s):  
Kuo-I Lin ◽  
Yi Lin ◽  
Kathryn Calame
Keyword(s):  
Cell Differentiation ◽  
Target Genes ◽  
Ectopic Expression ◽  
Constitutive Expression ◽  
Dominant Negative ◽  
B Cell Differentiation ◽  
Dominant Negative Form ◽  
Proliferation And Differentiation ◽  
Negative Form

ABSTRACT The importance of c-myc as a target of the Blimp-1 repressor has been studied in BCL-1 cells, in which Blimp-1 is sufficient to trigger terminal B-cell differentiation. Our data show that Blimp-1-dependent repression of c-myc is required for BCL-1 differentiation, since constitutive expression of c-Myc blocked differentiation. Furthermore, ectopic expression of cyclin E mimicked the effects of c-Myc on both proliferation and differentiation, indicating that the ability of c-Myc to drive proliferation is responsible for blocking BCL-1 differentiation. However, inhibition of c-Myc by a dominant negative form was not sufficient to drive BCL-1 differentiation. Thus, during Blimp-1-dependent plasma cell differentiation, repression of c-myc is necessary but not sufficient, demonstrating the existence of additional Blimp-1 target genes.

MicroRNAs and their role in hematological malignant diseases

2012 ◽  
Vol 153 (52) ◽  
pp. 2051-2059 ◽  
Author(s):  
Zsuzsanna Gaál ◽  
Éva Oláh
Keyword(s):  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Cancer Tissue ◽  
Altered Expression ◽  
Diagnosis And Prognosis ◽  
Oncologic Patients ◽  
Different Types ◽  
Non Coding Rnas ◽  
Success Of Treatment ◽  
Posttranscriptional Level

MicroRNAs are a class of small non-coding RNAs regulating gene expression at posttranscriptional level. Their target genes include numerous regulators of cell cycle, cell proliferation as well as apoptosis. Therefore, they are implicated in the initiation and progression of cancer, tissue invasion and metastasis formation as well. MicroRNA profiles supply much information about both the origin and the differentiation state of tumours. MicroRNAs also have a key role during haemopoiesis. An altered expression level of those have often been observed in different types of leukemia. There are successful attempts to apply microRNAs in the diagnosis and prognosis of acute lymphoblastic leukemia and acute myeloid leukemia. Measurement of the expression levels may help to predict the success of treatment with different kinds of chemotherapeutic drugs. MicroRNAs are also regarded as promising therapeutic targets, and can contribute to a more personalized therapeutic approach in haemato-oncologic patients. Orv. Hetil., 2012, 153, 2051–2059.

MicroRNA Determines the Fate of Intestinal Epithelial Cell Differentiation and Regulates Intestinal Diseases

2019 ◽  
Vol 20 (7) ◽  
pp. 666-673 ◽  
Author(s):  
Sujuan Ding ◽  
Gang Liu ◽  
Hongmei Jiang ◽  
Jun Fang
Keyword(s):  
Target Genes ◽  
Gastrointestinal Disease ◽  
Intestinal Barrier ◽  
Vital Role ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Intestinal Function ◽  
Cell Fates ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

The rapid self-renewal of intestinal epithelial cells enhances intestinal function, promotes the nutritional needs of animals and strengthens intestinal barrier function to resist the invasion of foreign pathogens. MicroRNAs (miRNAs) are a class of short-chain, non-coding RNAs that regulate stem cell proliferation and differentiation by down-regulating hundreds of conserved target genes after transcription via seed pairing to the 3' untranslated regions. Numerous studies have shown that miRNAs can improve intestinal function by participating in the proliferation and differentiation of different cell populations in the intestine. In addition, miRNAs also contribute to disease regulation and therefore not only play a vital role in the gastrointestinal disease management but also act as blood or tissue biomarkers of disease. As changes to the levels of miRNAs can change cell fates, miRNA-mediated gene regulation can be used to update therapeutic strategies and approaches to disease treatment.

scholarly journals miR-21-5p Regulates the Proliferation and Differentiation of Skeletal Muscle Satellite Cells by Targeting KLF3 in Chicken

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 814
Author(s):  
Donghao Zhang ◽  
Jinshan Ran ◽  
Jingjing Li ◽  
Chunlin Yu ◽  
Zhifu Cui ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Development ◽  
Target Genes ◽  
Cell Number ◽  
Sequencing Data ◽  
Proliferation Markers ◽  
Muscle Satellite Cells ◽  
Skeletal Muscle Satellite Cells ◽  
Proliferation And Differentiation

The proliferation and differentiation of skeletal muscle satellite cells (SMSCs) play an important role in the development of skeletal muscle. Our previous sequencing data showed that miR-21-5p is one of the most abundant miRNAs in chicken skeletal muscle. Therefore, in this study, the spatiotemporal expression of miR-21-5p and its effects on skeletal muscle development of chickens were explored using in vitro cultured SMSCs as a model. The results in this study showed that miR-21-5p was highly expressed in the skeletal muscle of chickens. The overexpression of miR-21-5p promoted the proliferation of SMSCs as evidenced by increased cell viability, increased cell number in the proliferative phase, and increased mRNA and protein expression of proliferation markers including PCNA, CDK2, and CCND1. Moreover, it was revealed that miR-21-5p promotes the formation of myotubes by modulating the expression of myogenic markers including MyoG, MyoD, and MyHC, whereas knockdown of miR-21-5p showed the opposite result. Gene prediction and dual fluorescence analysis confirmed that KLF3 was one of the direct target genes of miR-21-5p. We confirmed that, contrary to the function of miR-21-5p, KLF3 plays a negative role in the proliferation and differentiation of SMSCs. Si-KLF3 promotes cell number and proliferation activity, as well as the cell differentiation processes. Our results demonstrated that miR-21-5p promotes the proliferation and differentiation of SMSCs by targeting KLF3. Collectively, the results obtained in this study laid a foundation for exploring the mechanism through which miR-21-5p regulates SMSCs.

Glycans in scaffold design in tissue reconstruction

2021 ◽  
pp. 088391152199784
Author(s):  
Nipun Jain ◽  
Shashi Singh
Keyword(s):  
Cell Attachment ◽  
Low Cost ◽  
Growth Conditions ◽  
Downstream Signaling ◽  
Cell Carrier ◽  
Wide Range ◽  
Proliferation And Differentiation ◽  
Different Types ◽  
Tissue Reconstruction ◽  
A Cell

Development of an artificial tissue by tissue engineering is witnessed to be one of the long lasting clarified solutions for the damaged tissue function restoration. To accomplish this, a scaffold is designed as a cell carrier in which the extracellular matrix (ECM) performs a prominent task of controlling the inoculated cell’s destiny. ECM composition, topography and mechanical properties lead to different types of interactions between cells and ECM components that trigger an assortment of cellular reactions via diverse sensing mechanisms and downstream signaling pathways. The polysaccharides in the form of proteoglycans and glycoproteins yield better outcomes when included in the designed matrices. Glycosaminoglycan (GAG) chains present on proteoglycans show a wide range of operations such as sequestering of critical effector morphogens which encourage proficient nutrient contribution toward the growing stem cells for their development and endurance. In this review we discuss how the glycosylation aspects are of considerable importance in everyday housekeeping functions of a cell especially when placed in a controlled environment under ideal growth conditions. Hydrogels made from these GAG chains have been used extensively as a resorbable material that mimics the natural ECM functions for an efficient control over cell attachment, permeability, viability, proliferation, and differentiation processes. Also the incorporation of non-mammalian polysaccharides can elicit specific receptor responses which authorize the creation of numerous vigorous frameworks while prolonging the low cost and immunogenicity of the substance.

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