Expression of FOXP1 in a Poor Prognostic Sub-Group of DLBCL Is Associated with Deregulated Expression of AID.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2034-2034
Author(s):  
James A.L. Fenton ◽  
Sharon L. Barrans ◽  
Andrew S. Jack
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Expression Profiles ◽  
Ectopic Expression ◽  
B Cell Lymphoma ◽  
Cell Development ◽  
B Cell Development ◽  
Germinal Centre ◽  
Cell Phenotype

Abstract We have previously shown that strong, uniform expression of the transcription factor FOXP1 is associated with a poor outcome in a sub-group of activated (non-germinal centre) diffuse large B-cell lymphoma (DLBCL). To further define this poor prognostic group we have compared gene expression profiles of 10 cases which had either FOXP1 uniform, positive expression (n=6) or were FOXP1 negative (n=4). For all cases, a non-Germinal Centre (GC) B cell phenotype, namely CD10 negative, BCL6 negative, MUM1 positive, BCL2 positive, was matched as closely as possible between the two groups, with FOXP1 expression being the solitary differential factor. Gene expression profiling using Affymetrix U133 plus 2.0 chips was performed with RNA extracted from the 10 patient samples and differentially expressed genes were identified between the 2 groups following normalisation of the results. FOXP1 positive lymphoma cells were associated with a distinct expression pattern with activation-induced deaminase (AID) being the gene determined as having the biggest difference in expression, namely an approximately 60-fold increase in expression in FOXP1 positive samples. AID is associated with both the somatic hypermutation and class switch recombination processes of immunoglobulin heavy chain (IgH) genes of normal B-cells, being primarily expressed at the GC stage of B-cell development. An RT-PCR undertaken for AID expression of the 8 cases, where further RNA was still available, confirmed that AID expression was present in FOXP1 positive cases (n=5) but either absent or very weakly expressed in FOXP1 negative cases (n=3). PCR amplification of the IgH variable (V) gene of the sample from RNA, where successful was followed by sequence analysis which showed expected levels of mutation of at least 5% variation from germline IgH V genes. Intraclonal variation of the IgH V region genes was also examined in both FOXP1 positive and negative samples, there was no correlation between the expression of AID and the occurrence of SHM or even evidence of ongoing mutation. Reports have variably suggested that AID expression is confined to GC-type DLBCL, or is heterogeneous between GC and non GC-type (activated) DLBCL. Here we have demonstrated expression of AID in association with over-expression of FOXP1 in cases that are of post-GC origin. This would suggest that AID is deregulated, being expressed beyond the normal GC stage of B-cell differentiation. We hypothesise that FOXP1 positive DLBCL arise from cells at a specific phase of B-cell development. Normal B-cells expressing FOXP1 are found predominately in the mantle zone with a small number of cells in the GC. Ectopic expression of AID has been linked with tumour formation in mice, implying AID has oncogenic potential. Continued (or post-GC) deregulated expression of AID in these DLBCL cells may be a significant pathogenic event associated with these tumours. Normally AID is tightly regulated in B-cells, one vital function of this regulation may be to prevent lymphomagenesis. It is therefore conceivable that overexpression of FOXP1 in this poor prognostic subgroup of DLBCL results in deregulated expression of AID and is therefore a major contributing factor to lymphomagenesis.

New Pathogenetic Insights Into Classical Hodgkin Lymphoma Revealed by Gene Expression Profiling of Microdissected Hodgkin/Reed-Sternberg Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 266-266 ◽  
Author(s):  
Enrico Tiacci ◽  
Verena Brune ◽  
Susan Eckerle ◽  
Wolfram Klapper ◽  
Ines Pfeil ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Expression Profiling ◽  
Expression Profiles ◽  
B Cell Lymphoma ◽  
Cell Phenotype

Abstract Abstract 266 Background. Previous gene expression profiling studies on cHL have been performed on whole tissue sections (mainly reflecting the prominent reactive background in which the few HRS cells are embedded), or on cHL cell lines. However, cultured HRS cells do not likely reflect primary HRS cells in all aspects, being derived from end-stage patients and from sites (e.g. pleural effusions or bone marrow) which are not typically involved by cHL and where HRS cells lost their dependence on the inflammatory microenvironment of the lymph node. Methods. ∼1000–2000 neoplastic cells were laser-microdissected from hematoxylin/eosin-stained frozen sections of lymph nodes taken at disease onset from patients with cHL (n=16) or with various B-cell lymphomas (n=35), including primary mediastinal B-cell lymphoma (PMBL) and nodular lymphocyte-predominant Hodgkin lymphoma (nLPHL). After two rounds of in vitro linear amplification, mRNA was hybridized to Affymetrix HG-U133 Plus 2.0 chips. Expression profiles were likewise generated from sorted cHL cell lines and several normal mature B-cell populations. Results. Primary and cultured HRS cells, although sharing hallmark cHL signatures such as high NF-kB transcriptional activity and lost B-cell identity, showed considerable transcriptional divergence in chemokine/chemokine receptor activity, extracellular matrix remodeling and cell adhesion (all enriched in primary HRS cells), as well as in proliferation (enriched in cultured HRS cells). Unsupervised and supervised analyses indicated that microdissected HRS cells of cHL represent a transcriptionally unique lymphoma entity, overall closer to nLPHL than to PMBL but with differential behavior of the cHL histological subtypes, being HRS cells of the lymphocyte-rich and mixed-cellularity subtypes close to nLPHL cells while HRS cells of NS and LD exhibited greater similarity to PMBL cells. HRS cells downregulated a large number of genes involved in cell cycle checkpoints and in the maintenance of genomic integrity and chromosomal stability, while upregulating gene and gene signatures involved in various oncogenic signaling pathways and in cell phenotype reprogramming. Comparisons with normal B cells highlighted the lack of consistent transcriptional similarity of HRS cells to bulk germinal center (GC) B cells or plasma cells and, interestingly, a more pronounced resemblance to CD30+ GC B cells and CD30+ extrafollicular B cells, two previously uncharacterized subsets that are transcriptionally distinct from the other mature B-cell types. Conclusions. Gene expression profiling of primary HRS cells provided several new insights into the biology and pathogenesis of cHL, its relatedness to other lymphomas and normal B cells, and its enigmatic phenotype. Disclosures: No relevant conflicts of interest to declare.

Ectopic Expression of HDAC9 in Murine Lymphoid System Leads to Altered Lymphocyte Numbers and Proliferation as Well as Predisposition to Tumorigenesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 376-376
Author(s):  
Veronica S. Gil ◽  
Louise M.C. Howell ◽  
Jenny Yeung ◽  
Kevin R. Petrie ◽  
Adrian Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Ectopic Expression ◽  
Cell Development ◽  
B Cell Development ◽  
Gene Promoters ◽  
Marginal Zone B Cells ◽  
Lymphoid System

Abstract Reversible acetylation of lysine residues on histone tails is associated with changes to chromatin structure and plays a key role in regulation of gene expression. In this process, histone hypoacetylation is generally associated with gene silencing and pharmacological inhibition of histone deacetylases (HDACs) leads usually to activation of gene expression. Decreased histone acetylation is a hallmark of cancer cells and increased HDAC expression or their mistargetting to specific gene promoters has been associated with a variety of tumors. In the past we have identified and cloned class IIa HDAC9. The HDAC9 gene is located in chromosome 7p21, which is frequently amplified in B-cell tumours such as mantle cell lymphoma (MCL) and in B-cell non-Hodgkin’s lymphoma cell lines. Consistently, initial analysis of patient samples and/or publicly available microarray data highlighted high levels of HDAC9 expression in chronic lymphocytic leukemia, folicullar lymphoma and MCL. Within the normal lymphoid system, HDAC9 is co-expressed with BCL-6 in germinal center B-cells (∼60% of cells). HDAC9 is also expressed in marginal zone B cells and a fraction of CD38 or CD27 positive subepithelial tonsilar cells. In order to examine the role of HDAC9 in the lymphoid development and pathogenesis of lymphoid malignancies we used Ig heavy chain enhancer (Eμ), which drives gene expression from early stages of B-cell development, to ectopically express HDAC9 in transgenic mice. Hemizygous and homozygous mice expressing Flag epitope tagged human HDAC9 (fHDAC9) transgene display throughout their lifespan altered B-cell development. Immunophenotypic analysis of B-cells isolated from bone marrow (BM) revealed an absence of cells expressing the pre-B/immature-B cell markers normally associated with C-E Hardy’s fractions. In vitro functional clonogenic assays for IL-7 responsive BM-derived B-cell progenitors demonstrated an increase (∼50%) in colony numbers in the transgenic BM. Moreover, morphologic and flow cytometric analyses of the transgenic colonies, but not those derived from normal BM, revealed the presence of granulocyte/macrophage colony forming units expressing the HDAC9 transgene, suggesting a lympho-myeloid lineage switch. This correlates with the finding that extramedullary myelopoiesis occurs in a fraction of mice presenting splenomegaly (44%). Furthermore, a subgroup of homozygous Eμ-fHDAC9 mice (n=16) developed tumours (81%) at middle age, and present with enlarged lymph nodes (6%) and abnormal hematopoietic elements in peripheral blood and BM. Taken together these data suggest that HDAC9 plays a role in B-cell maturation and its ectopic expression in early B-cells leads to perturbation of normal B-cell development, possibly predisposing transgenic mice to tumorigenesis.

ABCG2 Is Expressed in a Small Population of Circulating CLL B-Cells Characterized by Expression of Self-Renewal and Early B-Cell Development Genes and Resistance to Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3156-3156 ◽  
Author(s):  
Grzegorz S. Nowakowski ◽  
Xiaosheng Wu ◽  
Jennifer L. Abrahamzon ◽  
Renee Tschumper ◽  
Neil E. Kay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
B Cells ◽  
B Cell ◽  
Residual Disease ◽  
Cell Development ◽  
Small Population ◽  
B Cell Development ◽  
Self Renewal ◽  
Resistance To Therapy

Abstract Background: Normal and tumor stem cells are characterized by high activity of multidrug resistance (MDR) transporters. One of these, ABCG2 (ATP-binding cassette, sub-family G member 2 protein), is an ATP dependent transporter and putative stem cell marker responsible for verapamil sensitive Hoechst efflux. While ABCG2 is known to be expressed in normal and leukemic stem cells, as well as a small population of normal lymphocytes and some B-cell malignancies, its expression in chronic lymphocytic leukemia (CLL) is unknown. It has been postulated that leukemic stem cells due to their quiescent nature and expression of MDR transporters represent a population resistant to therapy and that this residual population is critical for tumor persistence and recurrence. Hypothesis: We hypothesized that ABCG2 is expressed in a small percentage of primary CLL B cells; gene expression profiles of ABCG2 positive versus ABCG2 negative CLL B cells differ in respect to expression of self renewal and lymphoid development genes; the frequency of ABCG2+ CLL B cells increases after treatment in patients responding to therapy. Methods: We analyzed ABCG2 expression by primary CD5+, CD19+ CLL-B cells from untreated CLL patients of all Rai stages by flow cytometry. In a subset of patients we used fluorescence activated cell sorting (FACS) to sort CD19+, CD5+ ABCG2+ and CD19+, CD5+ ABCG2- cells. Gene expression profiling was then performed using the U133 plus 2.0 Affymetrix microarray platform. In a separate cohort of patients treated in a clinical trial of pentostatin, cyclophosphamide and rituximab (PCR), the percentage of ABCG2+, CD19+, CD5+, CD79b dim cells at baseline and then two months after completion of 6 cycles of PCR therapy where patients had minimal residual disease (MRD) was assessed and correlated with clinical response. Results: ABCG2+ CD19+, CD5+ detectable populations were seen in all 20 CLL assessed patients (median percentage 0.6%; range 0.08%–3.8%). There was no difference in percentage of ABCG2+ cells based on Rai stage, IGVH mutational status, Zap70 or CD38 expression. Preliminary analysis of the gene expression profiling of ABCG2 positive versus negative CLL B cells from four randomly selected patients revealed significantly higher expression of genes associated with self-renewal, cell cycle and early B-cell development including: cyclin-dependent kinase inhibitor 1C (CDKN1C, p=0.034), transcription factor 7-like 2 (TCF7L2, involved in WNT pathway regulation, p=0.016), beta-catenin (p=0.034) and pre-B-cell colony enhancing factor 1 (PBEF-1, p=0.037). Flow based assessment of the levels of ABCG2 positive populations at baseline and after therapy with PCR in patients with minimal residual disease showed a dramatic increase in frequency of ABCG2 positive CLL B cells. The percentage of ABCG2+ cells went from a median level of 0.19% (range 0.04%–0.19%) prior to therapy to a median level of 10.93% (range 0.15%–25.12%), p<0.001. In contrast two patients who did not reach MRD (partial responses by NCI-WG criteria) had no significant increase in percentage of ABCG2 positive cells (0.14%; 0.23% and 0.16%; 0.21% prior and after therapy, respectively, p=0.68). Conclusion: Our data indicate that ABCG2 positive CLL B-cells constitute 0.1–3.8% of circulating CLL B-cells in untreated patients. The frequency of ABCG2+ CLL B-cells appears to dramatically increase after therapy in the MRD state; this could be related to their relative resistance to therapy and/or a shift from extravascular compartments post therapy. Since ABCG2 positive CLL B-cells demonstrate expression of early B-cell development and self-renewal genes we believe that that this population could represent a putative self renewing CLL B-cell compartment. Further studies to characterize features of ABCG2 CLL-B –cells in relation to their capacity to be self renewing and resistance to therapy are warranted.

scholarly journals Essential role of EBF1 in the generation and function of distinct mature B cell types

2012 ◽  
Vol 209 (4) ◽  
pp. 775-792 ◽  
Author(s):  
Bojan Vilagos ◽  
Mareike Hoffmann ◽  
Abdallah Souabni ◽  
Qiong Sun ◽  
Barbara Werner ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Intracellular Signaling ◽  
Ectopic Expression ◽  
Cell Types ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Stage ◽  
Cell Immunity ◽  
Cell Commitment

The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro–B cell development, and subsequent transition to the pre–B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity.

Characterization of Early Human B Cell Development by Gene Expression Profiling.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1352-1352
Author(s):  
Marit E. Hystad ◽  
Trond H. Bo ◽  
Edith Rian ◽  
June H. Myklebust ◽  
Einar Sivertsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Populations ◽  
Early Human ◽  
Human B Cell

Abstract B cells develop from hematopoietic stem cells (HSC) in the bone marrow (BM) through a number of distinct stages before they migrate to the periphery as naïve mature B lymphocytes. These developmental stages can be identified by expression of cell surface antigens and Ig gene rearrangement status. The aim of this study was to characterize the earliest steps of normal human B cell development by gene expression profiling. Immunomagnetic selection and subsequent fluorescence-activated cell sorting (FACS) were used to isolate five populations from adult human BM: CD34+CD38− (HSC), CD34+CD10+CD19− early lymphoid progenitor cells (ELP), CD34+CD10+CD19+IgM− progenitor B cells (pro-B), CD34−CD10+CD19+IgM− precursor B cells (pre-B) and CD34−CD10+CD19+IgM+ immature B cells (IM). Total RNA was extracted from the purified cell populations, amplified and hybridized to Lymphochip cDNA microarrays. Six independent experiments from different donors were performed for each cell population. Expression of the genes encoding the selection markers confirmed the validity of the approach. Interestingly, genes necessary for the V(D)J-recombination such as RAG-1, RAG-2, TdT and ADA showed higher gene expression in the ELP population than in the HSC. In contrast, the transcription factors E2A, EBF, and Pax-5, which are all essential for early B-cell development, were first turned on in pro-B cells, in accordance with the B-cell lineage commitment. The ELP did not express B, T or NK lineage markers, except for a higher expression level of CD2 in the ELP population than in the four other cell populations. Taken together, the expression pattern of CD2 and the V(D)J-recombination genes in the ELP population, indicate that these cells have developed a lymphocyte potential, but are not fully committed to B-lineage cells. Hierarchical cluster analysis of the 758 differentially expressed genes (differences in relative expression by a factor of two or more and with maximum10% FDR) revealed a pattern that clearly separated the five consecutive cell populations. Furthermore, we created expression signatures based on information from Gene Ontology (GO) http://source.stanford.edu/cgi-bin/source/sourceSearch. One of the clearest distinctions between the gene expressions of the five developmental populations involved genes associated with proliferation, and showed that the HSC and IM populations are relatively indolent while the pro-B and pre-B populations comprised high expression levels of nearly all the proliferation associated genes. Finally, we examined in further detail the transitions between HSC, ELP and pro B cells. We found 25 genes to be differently expressed in the ELP population in comparison to the HSC and pro-B populations, including IGJ, BCL2 and BLNK. To identify combinations of markers that could better discriminate the ELP population, we also performed a gene pair class separation test. This resulted in 68 gene pairs with score above 10 that were denoted very good discriminators. For several of the markers the differences in gene expression were verified at the protein level by five colour FACS analysis. Taken together, these results provide new insight into the molecular processes that take place in the early human B cell differentiation, and in particular provide new information regarding expression of genes in the ELP population.

Constitutively Activated STAT3 Promotes Cell Proliferation and Survival in the Activated B Cell Subtype of Diffuse Large B Cell Lymphomas.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1621-1621
Author(s):  
Bihui Hilda Ye ◽  
Beibei Belinda Ding ◽  
Jian Jessica Yu ◽  
Raymond Y.-L. Yu ◽  
Lourdes M. Mendez ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
B Cell Lymphoma ◽  
Cell Development ◽  
B Cell Development ◽  
Reciprocal Relationship ◽  
B Cell Lymphomas ◽  
Large B Cell

Abstract During B cell development, cell proliferation and survival are regulated by stage-specific transcription factors. Accordingly, distinct oncogenic pathways are employed by B cell lymphomas representing different stages of B cell development. Diffuse large B cell lymphoma (DLBCL) contains at least two main phenotypic subtypes, i.e. the germinal center B cell-like (GCB-DLBCL) and the activated B cell-like (ABC-DLBCL) groups. It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated NF-kappaB and tends to be refractory to chemotherapy. In this study, we investigated the relationship between BCL6 and STAT3 expression/activation in DLBCL and normal GC B cells. Our results demonstrate that BCL6 directly inhibits transcription of the STAT3 gene by binding to two BCL6 sites in its 5′ regulatory region. As a result, high level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells. Specifically, in tonsillar GCs, STAT3 expression and activation is restricted to a previously uncharacterized subset of BCL6−Blimp-1− B cells in the apical light zone. The location and phenotype of these cells suggest that they are in the process of exiting the BCL6-directed GC program and transitioning to a plasma cell differentiation process governed by Blimp-1. The reciprocal relationship between BCL6 and STAT3 is also conserved in DLBCL such that STAT3 expression and activation is preferentially associated with the BCL6-low, ABC subtype. Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis. These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB and Mcl-1, and increased expression of the cell cycle inhibitor p27. In addition to identifying STAT3 as a novel BCL6 target gene, our results define STAT3 activation as a second oncogenic pathway operating in ABC-DLBCL and suggest that blocking STAT3 may be potentially therapeutic in treatment of these aggressive lymphomas.

scholarly journals Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4158-4169 ◽  
Author(s):  
Almut Meyer-Bahlburg ◽  
Shirly Becker-Herman ◽  
Stephanie Humblet-Baron ◽  
Socheath Khim ◽  
Michele Weber ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Selective Advantage ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Phenotype ◽  
Developmental Defect ◽  
In Vivo Models ◽  
Wiskott Aldrich Syndrome

Abstract To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro functional assays, we show that these deficits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that: (1) WASp expression levels increase with cell maturity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease.

scholarly journals Harnessing lymphoma epigenetics to improve therapies

Blood ◽  
2020 ◽  
Vol 136 (21) ◽  
pp. 2386-2391
Author(s):  
Haopeng Yang ◽  
Michael R. Green
Keyword(s):  
Transcription Factors ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Cell Development ◽  
B Cell Development ◽  
Affinity Maturation

Abstract Affinity maturation and terminal differentiation of B cells via the germinal center reaction is a complex multistep process controlled by transcription factors that induce or suppress large dynamic transcriptional programs. This occurs via the recruitment of coactivator or corepressor complexes that epigenetically regulate gene expression by post-translationally modifying histones and/or remodeling chromatin structure. B-cell–intrinsic developmental programs both regulate and respond to interactions with other cells in the germinal center that provide survival and differentiation signals, such as T-follicular helper cells and follicular dendritic cells. Epigenetic and transcriptional programs that naturally occur during B-cell development are hijacked in B-cell lymphoma by genetic alterations that directly or indirectly change the function of transcription factors and/or chromatin-modifying genes. These in turn skew differentiation toward the tumor cell of origin and alter interactions between lymphoma B cells and other cells within the microenvironment. Understanding the mechanisms by which genetic alterations perturb epigenetic and transcriptional programs regulating B-cell development and immune interactions may identify opportunities to target these programs using epigenetic-modifying agents. Here, we discuss recently published studies centered on follicular lymphoma and diffuse large B-cell lymphoma within the context of prior knowledge, and we highlight how these insights have informed potential avenues for rational therapeutic interventions.

scholarly journals The B29 (Immunoglobulin β-Chain) Gene Is a Genetic Target for Early B-Cell Factor

1999 ◽  
Vol 19 (1) ◽  
pp. 392-401 ◽  
Author(s):  
Peter Åkerblad ◽  
Maria Rosberg ◽  
Tomas Leanderson ◽  
Mikael Sigvardsson
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Chain Gene ◽  
Early B Cell Factor

ABSTRACT Early B-cell factor (EBF) is a transcription factor suggested as essential for early B-lymphocyte development by findings in mice where the coding gene has been inactivated by homologous disruption. This makes the identification of genetic targets for this transcription factor pertinent for the understanding of early B-cell development. The lack of B29 transcripts, coding for the β subunit of the B-cell receptor complex, in pro-B cells from EBF-deficient mice suggested that B29 might be a genetic target for EBF. We here present data suggesting that EBF interacts with three independent sites within the mouse B29 promoter. Furthermore, ectopic expression of EBF in HeLa cells activated a B29promoter-controlled reporter construct 13-fold and induced a low level of expression from the endogenous B29 gene. Finally, mutations in the EBF binding sites diminished B29 promoter activity in pre-B cells while the same mutations did not have as striking an effect on the promoter function in B-cell lines of later differentiation stages. These data suggest that the B29gene is a genetic target for EBF in early B-cell development.

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