scholarly journals Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259674
Author(s):  
Stefan Nagel ◽  
Corinna Meyer
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Target Genes ◽  
Lymphoid Cells ◽  
B Cell Differentiation ◽  
Aberrant Expression ◽  
T Box ◽  
Lymphoid Malignancies

T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells. The resultant expression pattern comprised six genes, namely EOMES, MGA, TBX1, TBX10, TBX19 and TBX21. We termed this gene signature TBX-code which enables discrimination of normal and aberrant activities of T-box genes in lymphoid malignancies. Accordingly, expression analysis of T-box genes in Hodgkin lymphoma (HL) patients using a public profiling dataset revealed overexpression of EOMES, TBX1, TBX2, TBX3, TBX10, TBX19, TBX21 and TBXT while MGA showed aberrant downregulation. Analysis of T-cell acute lymphoid leukemia patients indicated aberrant overexpression of six T-box genes while no deregulated T-box genes were detected in anaplastic large cell lymphoma patients. As a paradigm we focused on TBX3 which was ectopically activated in about 6% of HL patients analyzed. Normally, TBX3 is expressed in tissues like lung, adrenal gland and retina but not in hematopoiesis. HL cell line KM-H2 expressed enhanced TBX3 levels and was used as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line showed focal amplification of the TBX3 locus at 12q24 which may underlie its aberrant expression. In addition, promoter analysis and comparative expression profiling of HL cell lines followed by knockdown experiments revealed overexpressed transcription factors E2F4 and FOXC1 and chromatin modulator KDM2B as functional activators. Furthermore, we identified repressed target genes of TBX3 in HL including CDKN2A, NFKBIB and CD19, indicating its respective oncogenic function in proliferation, NFkB-signaling and B-cell differentiation. Taken together, we have revealed a lymphoid TBX-code and used it to identify an aberrant network around deregulated T-box gene TBX3 in HL which promotes hallmark aberrations of this disease. These findings provide a framework for future studies to evaluate deregulated T-box genes in lymphoid malignancies.

scholarly journals Establishment of the TALE-code reveals aberrantly activated homeobox gene PBX1 in Hodgkin lymphoma

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246603
Author(s):  
Stefan Nagel ◽  
Claudia Pommerenke ◽  
Corinna Meyer ◽  
Roderick A. F. MacLeod ◽  
Hans G. Drexler
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Lymphoid Cells ◽  
Aberrant Expression ◽  
Hematopoietic Stem

Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation and are grouped into classes and subclasses according to sequence similarities. Here, we analyzed the activities of the 20 members strong TALE homeobox gene class in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells (ILC). The resultant expression pattern comprised eleven genes and which we termed TALE-code enables discrimination of normal and aberrant activities of TALE homeobox genes in lymphoid malignancies. Subsequent expression analysis of TALE homeobox genes in public datasets of Hodgkin lymphoma (HL) patients revealed overexpression of IRX3, IRX4, MEIS1, MEIS3, PBX1, PBX4 and TGIF1. As paradigm we focused on PBX1 which was deregulated in about 17% HL patients. Normal PBX1 expression was restricted to hematopoietic stem cells and progenitors of T-cells and ILCs but absent in B-cells, reflecting its roles in stemness and early differentiation. HL cell line SUP-HD1 expressed enhanced PBX1 levels and served as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line therein showed a gain of the PBX1 locus at 1q23 which may underlie its aberrant expression. Comparative expression profiling analyses of HL patients and cell lines followed by knockdown experiments revealed NFIB and TLX2 as target genes activated by PBX1. HOX proteins operate as cofactors of PBX1. Accordingly, our data showed that HOXB9 overexpressed in HL coactivated TLX2 but not NFIB while activating TNFRSF9 without PBX1. Further downstream analyses showed that TLX2 activated TBX15 which operated anti-apoptotically. Taken together, we discovered a lymphoid TALE-code and identified an aberrant network around deregulated TALE homeobox gene PBX1 which may disturb B-cell differentiation in HL by reactivation of progenitor-specific genes. These findings may provide the framework for future studies to exploit possible vulnerabilities of malignant cells in therapeutic scenarios.

scholarly journals Assessing the role of the T-box transcription factor Eomes in B cell differentiation during either Th1 or Th2 cell-biased responses

PLoS ONE ◽  
2018 ◽  
Vol 13 (12) ◽  
pp. e0208343 ◽  
Author(s):  
Lucy Cooper ◽  
Lauren Hailes ◽  
Amania Sheikh ◽  
Colby Zaph ◽  
Gabrielle T. Belz ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
B Cell ◽  
B Cell Differentiation ◽  
T Box ◽  
Th2 Cell

scholarly journals Epigenetic Regulation of miR-92a and TET2 and Their Association in Non-Hodgkin Lymphoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Esther K. Elliott ◽  
Lloyd N. Hopkins ◽  
Robert Hensen ◽  
Heidi G. Sutherland ◽  
Larisa M. Haupt ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Target Genes ◽  
Cpg Islands ◽  
Mature Mirnas ◽  
Tumour Suppressor Genes ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Non Hodgkin Lymphoma

MicroRNAs (miRNAs) are well known for their ability to regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. In various cancers, miRNAs regulate gene expression by altering the epigenetic status of candidate genes that are implicated in various difficult to treat haematological malignancies such as non-Hodgkin lymphoma by acting as either oncogenes or tumour suppressor genes. Cellular and circulating miRNA biomarkers could also be directly utilised as disease markers for diagnosis and monitoring of non-Hodgkin lymphoma (NHL); however, the role of DNA methylation in miRNA expression regulation in NHL requires further scientific inquiry. In this study, we investigated the methylation levels of CpGs in CpG islands spanning the promoter regions of the miR-17–92 cluster host gene and the TET2 gene and correlated them with the expression levels of TET2 mRNA and miR-92a-3p and miR-92a-5p mature miRNAs in NHL cell lines, tumour samples, and the whole blood gDNA of an NHL case control cohort. Increased expression of both miR-92a-3p and miR-92a-5p and aberrant expression of TET2 was observed in NHL cell lines and tumour tissues, as well as disparate levels of dysfunctional promoter CGI methylation. Both miR-92a and TET2 may play a concerted role in NHL malignancy and disease pathogenesis.

scholarly journals IFI16Expression Is Related to Selected Transcription Factors during B-Cell Differentiation

2015 ◽  
Vol 2015 ◽  
pp. 1-20 ◽  
Author(s):  
Pier Paolo Piccaluga ◽  
Claudio Agostinelli ◽  
Fabio Fuligni ◽  
Simona Righi ◽  
Claudio Tripodo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
B Cell ◽  
Peripheral Blood Lymphocytes ◽  
B Cell Differentiation ◽  
Cellular Survival ◽  
Human B Cells ◽  
Proliferation And Differentiation ◽  
B Cell Subsets

The interferon-inducible DNA sensor IFI16 is involved in the modulation of cellular survival, proliferation, and differentiation. In the hematopoietic system, IFI16 is consistently expressed in the CD34+ stem cells and in peripheral blood lymphocytes; however, little is known regarding its regulation during maturation of B- and T-cells. We explored the role of IFI16 in normal B-cell subsets by analysing its expression and relationship with the major transcription factors involved in germinal center (GC) development and plasma-cell (PC) maturation.IFI16mRNA was differentially expressed in B-cell subsets with significant decrease inIFI16mRNA in GC and PCs with respect to naïve and memory subsets.IFI16mRNA expression is inversely correlated with a few master regulators of B-cell differentiation such asBCL6, XBP1, POU2AF1, andBLIMP1. In contrast,IFI16expression positively correlated withSTAT3, REL, SPIB, RELA, RELB, IRF4, STAT5B, andSTAT5A. ARACNE algorithm indicated a direct regulation ofIFI16byBCL6,STAT5B, andRELB, whereas the relationship betweenIFI16and the other factors is modulated by intermediate factors. In addition, analysis of the CD40 signaling pathway showed thatIFI16gene expression directly correlated with NF-κB activation, indicating that IFI16 could be considered an upstream modulator of NF-κB in human B-cells.

scholarly journals Genes Involved in the Transcriptional Regulation of Pluripotency Are Expressed in Malignant Tumors of the Uterine Cervix and Can Induce Tumorigenic Capacity in a Nontumorigenic Cell Line

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Graciela Ruiz ◽  
Heriberto A. Valencia-González ◽  
Delia Pérez-Montiel ◽  
Felipe Muñoz ◽  
Rodolfo Ocadiz-Delgado ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cell ◽  
Cell Line ◽  
Target Genes ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
Ectopic Expression ◽  
Normal Tissues

Transcription factors OCT4, SOX2, KLF4, C-MYC, and NANOG (OSKM-N) regulate pluripotency and stemness, and their ectopic expression reprograms human and murine fibroblasts that constitute the key of regenerative medicine. To determine their contribution to cell transformation, we analyzed the gene expression profiles of these transcription factors in cervical cancer samples and found that they are preferentially expressed in the tumor component. Also, cancer stem cell-enriched cultures grown as sphere cultures showed overexpression of OSKM-N genes. Importantly, we observed that lentiviral-mediated transduction of these factors confers, to a nontumorigenic immortalized human cell line, properties of cancer stem cells as the ability to form tumors in a mouse model. When we performed a meta-analysis using microarray data from cervical cancer biopsies and normal tissues, we found that the expression of OSKM-N and some target genes allowed separating tumor and normal tissues between samples, which enhanced the importance of OSKM-N in the tumorigenesis. Finally, we analyzed and compared both transcript and protein expression profiles of these factors within a cohort of patients with cervical cancer. To our knowledge, this is the first time that the expression of OSKM-N is described to induce one of the main characteristics of the cancer stem cell, the tumorigenicity. And, more importantly, its exogenous expression in a nontumorigenic cell line is sufficient to induce a tumorigenic phenotype; furthermore, the differential expression of this transcription factor distinguishes tumor tissue and normal tissue in cervical samples.

scholarly journals Identification of a B cell differentiation factor(s) spontaneously produced by proliferating T cells in murine lupus strains of the lpr/lpr genotype.

1983 ◽  
Vol 157 (2) ◽  
pp. 730-742 ◽  
Author(s):  
G J Prud'Homme ◽  
C L Park ◽  
T M Fieser ◽  
R Kofler ◽  
F J Dixon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Mouse Strain ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
B Cell Differentiation ◽  
Differentiation Factor ◽  
Cell Differentiation Factor

Lymph node and spleen cells of the autoimmune MRL/Mp-lpr/lpr mouse strain spontaneously produce (in the absence of mitogenic stimulation) a factor(s) that induces B cell differentiation. This factor is not produced by the congenic MRL/n mouse strain that lacks the lpr gene or by normal mouse strains. However, lymphoid cells of the B6-lpr/lpr (B6/1) strain also produce a B cell differentiation factor. Although the factor acts on resting B cells, its effect is greatly magnified by activating the B cells with anti-mu or lipopolysaccharide. MRL/l mice begin producing the factor as early as 1 mo of age but levels increase with age and appearance of lymphoproliferation. Cell depletion studies reveal that this factor is produced by T cells of the Lyt-1+2-phenotype. Because of its association with the lpr/lpr genotype, we term this B cell differentiation factor L-BCDF. Functional analysis of L-BCDF reveals that it acts regardless of cell density in culture and in the absence of interleukin 2 (IL-2). In fact, the increase in the production of L-BCDF by MRL/1 T cells with aging occurs concomitantly with a marked decrease in their ability to produce IL-2. No T cell replacing factor activity or B cell growth factor-like activity can be detected in MRL/l-derived supernatants. L-BCDF induces both IgM and IgG synthesis in lipopolysaccharide-activated B cells; however, it has a greater effect on IgG secretion. In particular, the production of IgG1, IgG2a, and IgG2b are markedly enhanced in the presence of L-BCDF. The spontaneous production of L-BCDF by T cells of SLE mice of lpr/lpr genotype suggests an association of this factor with autoimmunity.

Inhibition of Signal Transducer and Activator of Transcription 6 Activity in the Hodgkin Lymphoma Cell Line L1236 Induces Growth Inhibition and Apoptosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4593-4593
Author(s):  
Cheng Liu ◽  
Margareta Andersson ◽  
Dawei Xu ◽  
Hans-Erik Claesson ◽  
Magnus Bjorkholm ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Target Genes ◽  
Signal Transducer ◽  
Autocrine Growth ◽  
Regulated Expression ◽  
Hodgkin Lymphoma Cell ◽  
Interfering Rna

Abstract Signal transducer and activator of transcription 6 (STAT6) plays a central role in interleukin (IL)-4 and -13 signaling. Upon binding of the cognate receptors by these cytokines, STAT6 becomes phosphorylated by Jak family kinases and subsequently translocates to the nucleus where transcription of its target genes is regulated. Expression of IL-13 and its receptor are common features of Hodgkin lymphoma (HL) tumor cells, the so-called Hodgkin Reed-Sternberg (H-RS) cells, in which this cytokine has been shown to act as an autocrine growth factor. Consequently, constitutively phosphorylated STAT6 with a nuclear localization is a common and distinctive feature of H-RS cells in classical HL. We knocked down STAT6 expression in the HL cell line L1236 with small interfering RNA (siRNA) and found that inhibition of STAT6 activity results in cell growth inhibition, decreased viability and increased apoptosis. The results depict a central role of STAT6 in the growth of H-RS cells and indicate that STAT6 could be a potential target for therapeutic intervention in HL. Moreover, in order to identify the target genes of this transcription factor in H-RS cells, a combined approach of RNA interference and microarray is performed and the results will be presented.

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