POU2AF1

Gene Summary

Gene:POU2AF1; POU class 2 associating factor 1
Aliases: BOB1, OBF1, OCAB, OBF-1
Location:11q23.1
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:POU domain class 2-associating factor 1
HPRD
Source:NCBIAccessed: 18 March, 2015

Ontology:

What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 18 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Nucleic Acid Regulatory Sequences
  • Cancer Gene Expression Regulation
  • Octamer Transcription Factor-1
  • Leukaemia
  • Molecular Sequence Data
  • DNA-Binding Proteins
  • Vesicular Transport Proteins
  • Transfection
  • Chromosomes, Artificial, Bacterial
  • Chromosome Mapping
  • Octamer Transcription Factor-2
  • Transcription Factors
  • Zinc Fingers
  • PAX5
  • Immunoglobulin Heavy Chains
  • BCL6
  • Messenger RNA
  • Mutation
  • Multiple Myeloma
  • Trans-Activators
  • Immunoglobulins
  • Proto-Oncogene Proteins
  • Immunohistochemistry
  • B-Cell Lymphoma
  • Tumor Virus Infections
  • Base Sequence
  • Single Nucleotide Polymorphism
  • Triazoles
  • Succinate Dehydrogenase
  • Gene Enhancer Elements
  • B-Lymphocytes
  • CD Antigens
  • Translocation
  • FISH
  • Hodgkin Lymphoma
  • Chromosome 11
  • Promoter Regions
  • Cloning, Molecular
  • Exons
  • Transcription
  • Polymerase Chain Reaction
Tag cloud generated 18 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: POU2AF1 (cancer-related)

Huang J, Wang L, Jiang M, et al.
AGR2-mediated lung adenocarcinoma metastasis novel mechanism network through repression with interferon coupling cytoskeleton to steroid metabolism-dependent humoral immune response.
Cell Immunol. 2014; 290(1):102-6 [PubMed] Related Publications
7 anterior gradient homolog 2 (AGR2)-inhibited different molecular mutual positive correlation network was constructed in lung adenocarcinoma compared with human normal adjacent tissues by 17 overlapping molecules of 358 GRNInfer and 19 Pearson (AGR2 CC⩽-0.25). Based on GO, KEGG, GenMAPP, BioCarta and disease databases, we determined AGR2-mediated lung adenocarcinoma metastasis through repression with cytoskeleton of MAST1; steroid metabolism of SOAT2; humoral immune response of POU2AF1; interferon alpha-inducible of IFI6; immunoglobulin of IGKC_3, CTA_246H3.1. Thus we proposed AGR2-mediated lung adenocarcinoma metastasis novel mechanism network through repression with interferon coupling cytoskeleton to steroid metabolism-dependent humoral immune response.

Zhou Y, Liu X, Xu L, et al.
Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over-expression of the ETS factor SPIB in Waldenström macroglobulinaemia.
Br J Haematol. 2014; 166(5):677-89 [PubMed] Related Publications
In Waldenström macroglobulinaemia (WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID2 were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells (LPC). Ectopic expression of SPIB in healthy donor CD19(+) cells inhibited plasmacytic differentiation in conjunction with decreased transcription of IRF4 and XBP1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM1, XBP1 spliced form, IRF4 and ID2. Knock-down of SPIB also led to decreased BCL2 expression. Given that SPIB is a direct target of POU2AF1 (OBF1) in complex with POU2F2 or POU2F1, we next examined their expression in WM LPC. POU2F2 transcription, as well as POU2F2 and POU2AF1 protein expression was higher in WM LPC. Ectopic expression of POU2F2 in healthy donor CD19(+) cells induced transcription of SPIB and suppressed transcription of PRDM1 and IRF4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2AF1 in SPIB and ID2 promoters. These findings establish a molecular hierarchy among POU2F2, SPIB and ID2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM.

Chapuy B, McKeown MR, Lin CY, et al.
Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.
Cancer Cell. 2013; 24(6):777-90 [PubMed] Free Access to Full Article Related Publications
Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.

Johnson RC, Ma L, Cherry AM, et al.
B-cell transcription factor expression and immunoglobulin gene rearrangement frequency in acute myeloid leukemia with t(8;21)(q22;q22).
Am J Clin Pathol. 2013; 140(3):355-62 [PubMed] Related Publications
OBJECTIVES: To assess a large series of patients with acute myeloid leukemia (AML) with t(8;21) for both IGH@ and IGK@ B-cell gene rearrangements and for expression of PAX5, OCT2, and Bob.1 by immunohistochemistry and expression of CD19, CD79a, CD20, and CD22 by flow cytometry immunophenotyping.
METHODS: A total of 48 cases of AML with t(8;21)(q22;q22) were evaluated by immunohistochemistry and/or heavy chain and light chain immunoglobulin rearrangement studies where paraffin-embedded and/or fresh frozen material was available for study; previously performed flow cytometry studies were also reviewed in available cases.
RESULTS: Our study yielded 1 of 19 cases of AML with t(8;21) with an IGH@ gene rearrangement; blasts were associated with weak PAX5 expression. In addition, expression of antigens CD79a by flow cytometry and OCT2 by immunohistochemistry were highly associated with PAX5 expression, and CD19 was expressed in most cases assessed.
CONCLUSIONS: Although B-cell antigen and B-cell transcription factor expression is seen in the majority of AMLs with t(8;21)(q22;q22) and correlates with PAX5 expression, immunoglobulin gene rearrangements are an uncommon event in this group of leukemias.

Kanzawa M, Hirai C, Morinaga Y, et al.
Primary submucosal nodular plasmacytoma of the stomach: a poorly recognized variant of gastric lymphoma.
Diagn Pathol. 2013; 8:30 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Gastric plasmacytoma (GP) is a rare variant of gastric lymphomas. In the exceptional event that a patient presents with GP, the lesion occupies the mucosal layer in the vast majority of cases. Here we report a case of nodular plasmacytoma confined to the submucosa with no evidence of Helicobacter pylori (Hp) infection. The patient was a 59-year old female presenting with no particular symptoms. The tumor was well-demarcated and consisted of a diffuse monomorphic proliferation of plasma cells with numerous lymphoid follicles scattered throughout the tumor. The mucosal surface was intact and not associated with any tumor nodules. The cells were diffusely positive for CD79a, Bob1, EMA and IgA and consistently negative for CD3, CD19, CD20, PAX5, CD56, IgM and IgG. Additionally, in situ hybridization demonstrated clonality in the form of λ light-chain restriction. This submucosal nodular proliferation pattern of plasmacytoma is poorly recognized and considered to be a novel variant of lymphoma.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3489998708673079.

Toman I, Loree J, Klimowicz AC, et al.
Expression and prognostic significance of Oct2 and Bob1 in multiple myeloma: implications for targeted therapeutics.
Leuk Lymphoma. 2011; 52(4):659-67 [PubMed] Related Publications
The B/plasma cell transcription factor Oct2 and its co-activator Bob1 activate the immunoglobulin heavy chain (IgH) gene enhancer. IgH translocations occur in the majority of myeloma cases, leading to overexpression of genes juxtaposed to the IgH enhancers. We hypothesized that Oct2 and Bob1 are determinants of disease behavior and potential therapeutic targets in myeloma. Oct2 and Bob1 gene expressions were measured in CD138+ plasma cells and CD138-cells from bone marrow samples from patients with myeloma (n = 37); gene expression of Oct2 and Bob1 was higher in CD138+ than in CD138-cells (p < 0.0001). Oct2 and Bob1 protein expressions were assessed in bone marrow tissue microarrays from patients with myeloma (n = 169) with fluorescent immunohistochemistry, and correlated to patient survival. High Oct2 protein expression correlated with reduced survival (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.11-2.73, p = 0.0164), whereas high Bob1 protein expression correlated with increased survival (HR 0.46, 95% CI 0.29-0.71, p = 0.0008). Oct2 should be explored as a potential selective therapeutic target in myeloma.

Poretti G, Kwee I, Bernasconi B, et al.
Chromosome 11q23.1 is an unstable region in B-cell tumor cell lines.
Leuk Res. 2011; 35(6):808-13 [PubMed] Related Publications
Chromosome 11q23 region is a frequent target of chromosome aberrations in B-cell lymphoid tumors. Here, we present the cytogenetic and molecular characterization of an amplification affecting 11q23.1 in four cell lines derived from B-cell lymphoid tumors. A minimal common region of amplification of 330 kb was identified in three cell lines using Affymetrix Human Mapping 250K arrays. When analyzed with three BAC clones, the amplifications appeared different at cytogenetic level in each cell line. Possibly affected transcripts were evaluated using tiling arrays, and validated by real time PCR. Since no effect of the amplification at the local transcription level was observed, it is possible that 11q23 amplification might mainly represent the effect of unstable chromosomal region.

Carbone A, Gloghini A, Aiello A, et al.
B-cell lymphomas with features intermediate between distinct pathologic entities. From pathogenesis to pathology.
Hum Pathol. 2010; 41(5):621-31 [PubMed] Related Publications
Published in September 2008, the updated World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues introduces provisional borderline categories for lymphoma cases that demonstrate overlapping clinical, morphological, and/or immunophenotypic features between well-established entities. These overlapping features pose real diagnostic challenges especially in identifying atypical cases of diffuse large B-cell lymphoma, Hodgkin lymphoma, and Burkitt lymphoma. Lymphoma cases showing borderline features between T-cell/histiocyte-rich large B-cell lymphoma and nodular lymphocyte predominant Hodgkin lymphoma are not included within the borderline categories provisionally recognized by the updated classification. Within the borderline categories, there are cases combining features of primary mediastinal large B-cell lymphoma and classical Hodgkin lymphoma. Many of these cases resemble classical Hodgkin lymphoma but have a large number of tumor cells expressing CD20, CD45, and B-cell transcription factors. Alternatively, these cases may resemble primary mediastinal large B-cell lymphoma but contain tumor cells resembling Reed-Sternberg cells and displaying an aberrant phenotype such as CD20(-), CD15(-/+) CD45(+), CD30(+), Pax5(+), OCT2(+/-), and BOB1(+/-). Another new borderline category defining B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, represents a biologically heterogeneous group. Cases with morphologic features intermediate and with CD10/BCL6 coexpression should be placed in diffuse large B-cell lymphoma/Burkitt lymphoma category if tumor cells also show strong BCL2 staining and/or a Ki67 proliferation index of less than 90%. When MYC rearrangements are present in these cases, the lymphomas often have atypical features, including concurrent rearrangements of BCL2 and/or BCL6 genes (so-called double/triple-hit lymphomas) and more aggressive behavior. For the provisional borderline categories, unresolved issues include understanding molecular pathogenesis and defining an effective treatment.

Advani AS, Lim K, Gibson S, et al.
OCT-2 expression and OCT-2/BOB.1 co-expression predict prognosis in patients with newly diagnosed acute myeloid leukemia.
Leuk Lymphoma. 2010; 51(4):606-12 [PubMed] Related Publications
OCT-2 and its co-activator, BOB.1, are B-cell associated transcription factors expressed in a subset of patients with acute myeloid leukemia (AML). We evaluated OCT-2 and BOB.1 expression by immunohistochemistry in patients with newly diagnosed AML. The median overall survival (OS) for patients with varying levels of OCT-2 expression was statistically different (p = 0.03) (OCT-2 <10%: 21.7 months; OCT-2 10-50%: 18.4 months; OCT-2 >50%: 11.6 months). On multivariate analysis, co-expression of OCT-2/BOB.1 remained predictive for achievement of complete remission (HR 0.44, p = 0.010) and increased risk of relapse (HR 2.30, p = 0.047). OCT-2 (per 10% increase) was associated with a decreased progression-free survival (HR 1.10, p = 0.036) and a trend toward a worse OS (HR 1.10, p = 0.063). OCT-2 may act as a cell survival factor in AML by mediating expression of downstream targets, such as BCL-2. These results will need to be validated prospectively.

Smuk G, Illés A, Keresztes K, et al.
Pheno- and genotypic features of Epstein-Barr virus associated B-cell lymphoproliferations in peripheral T-cell lymphomas.
Pathol Oncol Res. 2010; 16(3):377-83 [PubMed] Related Publications
Among the 300 peripheral T-cell lymphomas (PTCL) searched for EBV positive non-resting B-cells by EBER in situ hybridization 12 have been identified with various forms of EBV-driven B-cell proliferation. This could be categorized into three major forms. i. In the first form scattered immature, mononuclear B-cells of immuno-, centroblastic type with CD20+. CD30+ CD45+, LMP1+ phenotype, reactive appearance and polyclonal immunoglobulin heavy chains gene rearrangement (IgH-R) were admixed to the PTCL cells. ii. The second form mimicked diffuse large B-cell lymphoma as homogenous sheets, largely demarcated from the PTCL, of mononuclear, immature B-cell of CD20+, CD30+, CD45+, LMP1+, EBNA-2+ phenotype but with lack of monoclonal IgH-R were present. iii. In the third form scattered Hodgkin-Reed-Sternberg (HRS) type of cells were noticed which exhibited the CD15+/-, CD20-/+, CD30+, CD45-, LMP1+, EBNA-2- phenotype and in 50% showed clonal IgH gene rearrangement in whole tissue DNA extract. The IgH associated transcription factors' (OCT2, BOB.1/OBF.1, PU.1) expression patterns in these cells corresponded to those of HRS cells in cHL. Based on analysis of 65 PTCLs, we have identified in the positive cases a highly significant increase of EBV+ small, reactive, resting B-cell compartment (75.9 / 100 HPF in PTCL vs. 1.5 / 100 HPF in control lymph nodes) likely to be due to the decreased immune surveillance. This progressive accumulation of EBV+ by-stander B-cell population in PTCLs might be the source of various B-cell proliferations, which in any form represent major diagnostic pitfalls and require a careful differential diagnostic procedure.

Pittman AM, Webb E, Carvajal-Carmona L, et al.
Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.
Hum Mol Genet. 2008; 17(23):3720-7 [PubMed] Related Publications
The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

Duan H, Xiang H, Ma L, Boxer LM
Functional long-range interactions of the IgH 3' enhancers with the bcl-2 promoter region in t(14;18) lymphoma cells.
Oncogene. 2008; 27(53):6720-8 [PubMed] Free Access to Full Article Related Publications
To better understand the mechanisms underlying the role of the immunoglobulin heavy-chain gene (IgH) 3' enhancers on bcl-2 transcriptional deregulation in t(14;18) lymphoma, we characterized the physical interactions of the IgH 3' enhancer region with the bcl-2 promoters. Using the chromosome conformation capture technique, we found that the IgH 3' enhancers physically interact with the bcl-2 promoter region over a 350 kb genomic region in t(14;18) lymphoma cells. No interactions of the bcl-2 promoter region with sequences distant to the IgH enhancers were observed. The physical interactions of the IgH enhancers with the bcl-2 5' region are functionally involved in the transcriptional control of bcl-2. The histone deacetylase inhibitor, trichostatin A, repressed bcl-2 transcription and decreased the IgH enhancer-bcl-2 promoter region interactions. We showed by chromatin immunoprecipitation assay and small interference RNA transfection studies that the POU2 family transcription factor Oct-2 and its cofactor Bob-1 have an important function in mediating the IgH enhancer-bcl-2 promoter region interactions. This study reveals a new aspect of the regulatory role of the IgH 3' enhancers on bcl-2 transcription in t(14;18) lymphomas.

Gashaw I, Dushaj O, Behr R, et al.
Novel germ cell markers characterize testicular seminoma and fetal testis.
Mol Hum Reprod. 2007; 13(10):721-7 [PubMed] Related Publications
Seminomas are characterized by expression of several stem cell markers, supporting their origin from germ cells. The current study focuses on novel germ cell markers in normal testes compared to those in fetal testes and different progression stages of seminomas. Microarray data were followed by RT-PCRs and immunohistochemistry on pure seminomas (pT1 to pT3) compared to adult and fetal testis. An upregulation of known germ cell markers, KIT, OCT4 and NANOG, was confirmed in seminoma specimens. We also identified novel germ cell markers such as BOB1 (POU2AF1, OBF1) and prominin 1 (PROM1, CD133), which were significantly upregulated in seminoma specimens, compared to normal testes. Furthermore, two Sertoli cell markers, SCGF (SCF) and the newly identified neuronal stem cell factor, MCFD2 (SDNSF), were expressed in seminoma cells. While BOB1 was expressed in fetal testis of second and third trimester of gestation, MCFD2 and PROM1 were only present in gonocytes up to the second trimester. All marker genes investigated were not further regulated in progressing tumour stages between pT1 and pT3. In conclusion, the germ cell markers described here provide evidence for the origin of seminoma cells, which could be from the developmental stage of early gonocytes or from spermatogonia re-expressing markers of the developing germ cells.

Zhao C, Inoue J, Imoto I, et al.
POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17.
Oncogene. 2008; 27(1):63-75 [PubMed] Related Publications
Multiple myeloma (MM), a progressive hematological neoplasm, is thought to result from multiple genetic events affecting the terminal plasma cell. However, genetic aberrations related to MM are seldom reported. Using our in-house array-based comparative genomic hybridization system to locate candidate target genes with following their expression analysis, we identified POU2AF1 at 11q23.1 as a probable amplification target in MM cell lines. POU2AF1 is a B-cell-specific transcriptional co-activator, which interacts with octamer-binding transcription factors Oct-1 and Oct-2, and augments their function. Downregulation of POU2AF1 expression by specific small-interfering RNA (siRNA) inhibited MM cell growth, whereas ectopic expression of POU2AF1 promoted growth of MM cells. Among putative transcriptional targets for POU2AF1, B-cell maturation factor, TNFRSF17, enhanced its transcription by POU2AF1, and POU2AF1 directly bound to an octamer site within the 5' region of TNFRSF17. Expression level of TNFRSF17 was closely correlated with that of POU2AF1 in cell lines and primary samples of MM, and decreasing TNFRSF17 expression by means of TNFRSF17 siRNA inhibited MM cell growth. Taken together, our results suggest that POU2AF1, when activated by amplification or other mechanisms, may contribute to progression of MM by accelerating growth of MM cells through direct transactivation of one of its target genes, TNFRSF17.

Tamaru J, Tokuhira M, Nittsu N, et al.
Hodgkin-like anaplastic large cell lymphoma (previously designated in the REAL classification) has same immunophenotypic features to classical Hodgkin lymphoma.
Leuk Lymphoma. 2007; 48(6):1127-38 [PubMed] Related Publications
In the WHO classification, the majority of Hodgkin-like ALCL cases as defined by the REAL classification are considered to be CHL. However, establishing a histological diagnosis for the gray zone between CHL and ALCL is often confusing. In this study, we re-evaluated such cases by performing immunohistochemistry with antibodies against PAX-5/BSAP, Oct.2, and BOB.1/OBF.1. Expression of PAX-5/BSAP was observed in 88% (76/87) of CHL specimens and none (0/11) of ALK-positive ALCL specimens. Among specimens of Hodgkin-like ALCL and ALK-negative ALCL, expression of PAX-5/BSAP was observed in 77% (20/26) and 18% (3/17), respectively. Most of the PAX-5/BSAP-positive specimens were negative for Oct.2 and/or BOB.1/OBF.1 except for four CHL specimens. Our results may support the WHO classification in which most cases of Hodgkin-like ALCL are classified as CHL. However, the patients with Hodgkin-like ALCL with CHL-immunophenotype (PAX-5/BSAP-positive and negative for Oct.2 and/or BOB.1) did not have a favorable outcome, with a 5-year OS rate of 58%.

Ushmorov A, Leithäuser F, Sakk O, et al.
Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma.
Blood. 2006; 107(6):2493-500 [PubMed] Related Publications
Many B-lineage-specific genes are down-regulated in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We investigated the involvement of epigenetic modifications in gene silencing in cHL cell lines and in microdissected primary HRS cells. We assessed the expression and methylation status of CD19, CD20, CD79B, SYK, PU.1, BOB.1/OBF.1, BCMA, and LCK, all of which are typically down-regulated in cHL. We could reactivate gene expression in cHL cell lines with the DNA demethylating agent 5-aza-deoxycytidine (5-aza-dC). Using methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and digestion with methylation-sensitive endonuclease followed by polymerase chain reaction (PCR), we determined the methylation status of promoter regions of PU.1, BOB.1/OBF.1, CD19, SYK, and CD79B. Down-regulation of transcription typically correlated with hypermethylation. Using bisulfite genomic sequencing we found that in microdissected HRS cells of primary cHL SYK, BOB.1/OBF.1, and CD79B promoters were also hypermethylated. Ectopic expression of both Oct2 and PU.1 in a cHL cell line potentiated endogenous PU.1 and SYK expression after 5-aza-dC treatment. These observations indicate that silencing of the B-cell-specific genes in cHL may be the consequence of a compromised regulatory network where down-regulation of a few master transcription factors results in silencing of numerous genes.

Heckman CA, Duan H, Garcia PB, Boxer LM
Oct transcription factors mediate t(14;18) lymphoma cell survival by directly regulating bcl-2 expression.
Oncogene. 2006; 25(6):888-98 [PubMed] Related Publications
Oct-1 and Oct-2 are members of the POU homeodomain family of transcriptional regulators and are critical for normal embryonic development. Gene-targeting studies showed that Oct-1 and Oct-2 are largely dispensable for B-cell development and immunoglobulin production, although both Oct-2 and Bob-1 are required for a proper immune response and germinal center formation. In these studies, we investigated the role of Oct factors in B-cell lymphomas. Recent investigations have shown increased expression of Oct-2 and Bob-1 in lymphomas, and we observed greatly increased levels of Oct-2 in lymphoma cells with the t(14;18) translocation. Decreased expression of Oct-1, Oct-2, or Bob-1 by RNA interference resulted in apoptosis and down-regulation of bcl-2 expression. Furthermore, Oct-2 induced bcl-2 promoter activity and mediated this effect through three regions in the bcl-2 P2 promoter. Although these regions did not contain canonical octamer motifs, we observed the direct interaction of Oct-2 with all three sites both in vitro by EMSA and in vivo by chromatin immunoprecipitation assay. Moreover, by mutation analysis we found that the ability of Oct-2 to activate bcl-2 required C/EBP, Cdx, and TATA-binding sites. Oct-2, therefore, acts as a cell survival factor in t(14;18) lymphoma cells by directly activating the antiapoptotic gene bcl-2.

Doerr JR, Malone CS, Fike FM, et al.
Patterned CpG methylation of silenced B cell gene promoters in classical Hodgkin lymphoma-derived and primary effusion lymphoma cell lines.
J Mol Biol. 2005; 350(4):631-40 [PubMed] Related Publications
Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) and primary effusion lymphoma (PEL) are derived from germinal center (GC) and post-GC B cells, respectively. Neither express many of the B cell genes or surface markers typically expressed by other GC-derived B cell lymphomas or normal B cells. This loss of B cell gene expression is not due to a lack of essential transcription factors, as studies have shown that the ectopic expression of missing transcription factors failed to reactivate endogenous target genes. These results implicate epigenetic mechanisms extinguishing B cell gene expression. Silenced endogenous B cell genes representing a surface receptor, B29 (Igbeta, CD79b), a signaling molecule, TCL1, and a transcription factor, Bob1 (OCA-B, OBF-1), were reactivated by 5-aza-2'-deoxycytidine, indicating that gene silencing in HRS and PEL cells is due to DNA methylation. Genomic bisulfite sequencing corroborated this prediction and revealed three distinct patterns of methylation for the silenced B29 and TCL1 promoters. These distinct patterns consisted of 5' promoter CpG methylation alone, 5' and 3' promoter CpG methylation sparing sites in the central cores, and complete CpG methylation throughout the promoter regions. The silenced Bob1 promoter showed one pattern of dense CpG methylation at essentially all sites. These consistent patterns predict that, although gene silencing in many HRS and PEL cells mimics appropriate gene silencing, in some cases of complete CpG methylation throughout entire promoters both the activation and targeting of methylation is abnormal.

Cavazzini F, De Wolf-Peeters C, Wlodarska I
Alterations of loci encoding PU.1, BOB1, and OCT2 transcription regulators do not correlate with their suppressed expression in Hodgkin lymphoma.
Cancer Genet Cytogenet. 2005; 158(2):167-71 [PubMed] Related Publications
Neoplastic cells of Hodgkin lymphoma (HL) originating from germinal or postgerminal center B cells lose their capacity to transcribe and to express surface immunoglobulins (Ig). This defect correlates with the absence of expression of B-cell-specific transcription regulators, including PU.1, BOB1, and OCT2. These findings suggest that Ig impairment in HL is caused by the defective transcription machinery. The mechanism or mechanisms underlying failure of Hodgkin cells to express PU.1, BOB1, and OCT2 remain unclear. The genes encoding for these three respective transcription factors have been mapped at 11p11.2 (SPI1), 11q23.1 (POU2AF1), and 19q13.2 (POU2F2); these are chromosomes recurrently affected in HL. To check the genomic status of PU.1, BOB1, and OCT2 in HL, we performed metaphase fluorescence in situ hybridization (FISH) analysis of 10 HL cases using locus-specific bacterial artificial chromosome clones. FISH signal pattern was correlated with the ploidy level of each analyzed cell and showed recurrent imbalances of the studied loci. The underrepresentation of one or two analyzed regions was detected in five cases; the remaining five cases showed either random losses, a ploidy-equivalent FISH pattern, or overrepresented signals. Neither a constant loss nor genomic aberration of at least one of these genes could be observed in studied cases. These findings indicate that genomic imbalances or rearrangements are not a cause of PU.1, BOB1, and OCT2 deficiency in cHL and argue for another mechanism underlying this phenomenon.

Ritz O, Leithäuser F, Hasel C, et al.
Downregulation of internal enhancer activity contributes to abnormally low immunoglobulin expression in the MedB-1 mediastinal B-cell lymphoma cell line.
J Pathol. 2005; 205(3):336-48 [PubMed] Related Publications
Primary mediastinal B-cell lymphoma (PMBL) is a highly aggressive tumour with a unique pattern of clinical, morphological, immunological and genetic features distinct from other diffuse large B-cell lymphomas. PMBLs are characterized by a mature B-cell phenotype, but they typically lack immunoglobulin (Ig) gene expression. The PMBL cell line MedB-1 shares many characteristic properties of the primary tumour, including low-level Ig production despite a functionally rearranged IgVH gene and absence of 'crippling' mutations. In this study, a search was undertaken for reasons for downregulated Ig expression. Similar levels of the B-cell-specific transcription factors BOB.1/OBF.1 and PU.1 were found in MedB-1 cells to those in the Ig-producing UM-1 lymphoblastoid cell line. However, MedB-1 lacked the Oct2 transcription factor. Reporter assays showed that Ig-type promoters were active in MedB-1 cells. In contrast, activity of the intronic heavy chain enhancer was dramatically reduced. Ectopic expression of Oct2 was able partially to restore enhancer activity but transcription from the endogenous IgVH gene could not be rescued. Therefore, the role of epigenetic factors in the downregulation of Ig was investigated. Methylated histone 3 lysine 9, a reliable marker of chromatin silencing, was not detected in MedB-1 promoter and enhancer regions. Inhibition of DNA methyltransferase and of histone deacetylases also did not reactivate Ig production. These data suggest the existence of alternative mechanisms of Ig inhibition in MedB-1 cells, different from chromatin silencing and the lack of Oct2.

Auer RL, Starczynski J, McElwaine S, et al.
Identification of a potential role for POU2AF1 and BTG4 in the deletion of 11q23 in chronic lymphocytic leukemia.
Genes Chromosomes Cancer. 2005; 43(1):1-10 [PubMed] Related Publications
Deletions of 11q in chronic lymphocytic leukemia (CLL) are usually associated with progressive disease and poor prognosis. A novel translocation within the previously identified 11q minimal region has been defined in a patient with CLL. The breakpoint is between genes POU2AF1 and BTG4. POU2AF1 is a B-cell-specific transcriptional coactivator, and BTG4 is a member of the BTG family of negative regulators of the cell cycle, making both of them good candidate genes for the pathogenesis of 11q- CLL. POU2AF1 was observed to be differentially expressed in the cells of patients with CLL compared to its expression in normal B cells in the absence of mutations. This may reflect ongoing stimulation and active accessory signaling in CLL cells. BTG4 could contribute to CLL pathogenesis following inactivation by haploinsufficiency.

Ushmorov A, Ritz O, Hummel M, et al.
Epigenetic silencing of the immunoglobulin heavy-chain gene in classical Hodgkin lymphoma-derived cell lines contributes to the loss of immunoglobulin expression.
Blood. 2004; 104(10):3326-34 [PubMed] Related Publications
Immunoglobulin production is impaired in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) in spite of functional clonal rearrangements. The presence of "crippling" mutations in coding and regulatory regions, as well as down-regulation of B-cell-specific transcription factors, has been suggested as a potential reason for the lack of immunoglobulin (Ig) chain gene transcription. We have investigated the impact of epigenetic silencing in suppressing Ig heavy (H)-chain expression. Chromatin immunoprecipitation (ChIP) was used to analyze transcription factor binding to octamer motifs present in the IgH regulatory regions. Transcription factors were bound to these motifs in control cell lines, however, they were absent in the cHL-derived cell lines KMH2, L1236, and L428. Ectopic expression of octamer-binding transcription factor (Oct2) and/or B-cell Oct binding protein/Oct-binding factor (BOB.1/OBF.1) did not result in any measurable binding to these sites. Increased histone 3 Lysine 9 (H3-K9) methylation was observed in the promoter region of the IgH locus in L428 and L1236 cells. This is a typical feature of heterochromatic, transcriptionally silent regions. Treatment of cHL-derived cell lines with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) partially reactivated IgH transcription and affected chromatin modifications. Our results suggest an important role of epigenetic silencing in the inhibition of IgH transcription in HRS cells.

García-Cosío M, Santón A, Martín P, et al.
Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma.
Mod Pathol. 2004; 17(12):1531-8 [PubMed] Related Publications
Hodgkin's lymphoma can be considered in most cases a B-cell lymphoma due to the presence of potentially functional immunoglobulin (Ig) gene rearrangements in the neoplastic cells. In contrast to lymphocyte-predominant Hodgkin's lymphoma, Hodgkin/Reed-Sternberg (HRS) cells from classical Hodgkin's lymphoma have low frequency of B-cell marker expression and lack Ig light and Ig heavy messenger RNA. Recent studies have shown transcription machinery deficiency in Hodgkin's lymphoma caused by an absence of the transcription factors OCT.1, OCT.2 and/or BOB.1. By using the tissue microarray technique, we have performed an immunohistochemical study of OCT.1, OCT.2 and BOB.1 in 325 classical Hodgkin's lymphoma cases. The results have been correlated with the expression of the B-cell markers CD20, CD79a, B-cell-specific activator protein (BSAP) and MUM.1, the presence of Epstein-Barr virus and the histological subtype. The percentage of CD20 and CD79a positivity was low (18 and 18%, respectively), whereas MUM.1 and BSAP were positive in the majority of cases. Considering the positive cases with independence of the intensity of staining, 62% of them expressed OCT.2, 59% OCT.1 and 37% BOB.1. Nevertheless, when we considered only the strongly positive cases, the results were similar to those previously described by others. No statistical association was found between the transcription factor expression, histological subtype and Epstein-Barr virus presence. To our knowledge, this is the largest series of classical Hodgkin's lymphoma cases in which the expression of transcription factors has been studied. We have found a notorious percentage of cases displaying weak positivity for OCT.2 and BOB.1 factors in HRS cells. We propose that other mechanisms different from the absence of transcription factors OCT.2 and BOB.1 might be involved in the control of Ig transcription and B lineage in classical Hodgkin's lymphoma.

Loddenkemper C, Anagnostopoulos I, Hummel M, et al.
Differential Emu enhancer activity and expression of BOB.1/OBF.1, Oct2, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas, and Hodgkin lymphomas.
J Pathol. 2004; 202(1):60-9 [PubMed] Related Publications
It has previously been demonstrated that in cultured and in situ tumour cells of classical Hodgkin lymphoma (cHL), the immunoglobulin (Ig) promoter is inactive and its transcription factors Oct2 and/or BOB.1/OBF.1 are down-regulated. In this study, the analysis of these transcription factors has been extended to a broad spectrum of B-cell malignancies and the findings have been related to the situation in normal B-cells of various differentiation stages and to the expression of Ig. Furthermore, an additional Ig transcription factor, PU.1, recently described to be absent from cHL, and a further regulatory element of the Ig gene, the intronic Emu enhancer, have been studied. BOB.1/OBF.1 and Oct2 were present in all B-cells expressing Ig, whereas PU.1 proved to be absent from late B-cell differentiation stages and from a subset of germinal centre B-cells. Interestingly, there were several normal (eg germinal centre centroblasts and monocytoid B-cells) and malignant B-cell populations (eg a proportion of diffuse large B-cell lymphomas, DLBCLs) that were Ig-negative, despite their BOB.1/OBF.1 and Oct2 expression. This study further shows that absence of PU.1 alone, as well as inactivation of the intronic Emu enhancer, is not sufficient to down-regulate Ig transcription. Taken together, the simultaneous absence of PU.1, Oct2, and/or BOB.1/OBF.1 is unique to Hodgkin and Reed-Sternberg (HRS) cells and cannot be detected in normal B-cell subsets or B-cell non-Hodgkin lymphomas (B-NHLs). This supports the concept that the down-regulation of Ig in cHL does not reflect a physiological situation, but a defect probably closely linked to the pathogenesis of cHL.

Salas M, Eckhardt LA
Critical role for the Oct-2/OCA-B partnership in Ig-secreting cells.
J Immunol. 2003; 171(12):6589-98 [PubMed] Related Publications
B and T lymphocytes arise from a common precursor in the bone marrow, but ultimately acquire very different functions. The difference in function is largely attributable to the expression of tissue-specific transcription factors that activate discrete sets of genes. In previous studies we and others have shown that the specialized genes expressed by Ig-secreting cells cease transcription when these cells are fused to a T lymphoma. The extinguished genes include those encoding Ig, J chain, and the transcription factors Oct-2, PU.1, and the coactivator OCA-B. Remarkably, if we sustain Oct-2 expression during cell fusion, all the other tissue-specific genes of the Ig-secreting cell simultaneously escape silencing. This suggests that Oct-2 plays a central role in maintaining the gene expression program of these cells. In the present studies we have investigated the roles of the transcription factor PU.1 and the coactivator OCA-B within the hierarchy of regulatory factors that sustain Ig-secreting cell function. Our results show that OCA-B and Oct-2 are regulatory partners in this process and that PU.1 plays a subordinate role at this cell stage.

Bräuninger A, Wacker HH, Rajewsky K, et al.
Typing the histogenetic origin of the tumor cells of lymphocyte-rich classical Hodgkin's lymphoma in relation to tumor cells of classical and lymphocyte-predominance Hodgkin's lymphoma.
Cancer Res. 2003; 63(7):1644-51 [PubMed] Related Publications
Hodgkin's lymphoma (HL) is separated into the classical (c) and lymphocyte-predominance (lp) forms. Whereas classical Hodgkin-Reed/Sternberg (HRS) cells carry mutated immunoglobulin (Ig) gene rearrangements that are often "crippled" and lack intraclonal diversity, and are likely derived from preapoptotic germinal center (GC) B cells, the lymphocytic and histiocytic cells of lpHL are presumably derived from selected GC B cells and often show ongoing somatic hypermutation. The recently identified lymphocyte-rich classical (lrc) HL is characterized by HRS cells with the immunophenotype of classical HRS cells (CD30(+)CD15(+)CD20(-)CD45(-)) but an infiltrate similar to lpHL and a clinical behavior resembling lpHL. To identify the histogenetic origin of the HRS cells in lrcHL and to determine the relationship to the lymphoma cells of cHL and lpHL we characterized seven cases of lrcHL by immunohistochemistry and sequenced the rearranged Ig genes of single micromanipulated HRS cells. The expression patterns of BCL6, CD138, Oct2, and BOB1 in HRS cells of lrcHL showed differences to those of both cHL and lpHL. Analyses of rearranged Ig genes identified clonal HRS cell expansions carrying mutated Ig rearrangements without significant intraclonal diversity in all seven of the cases. In two cases crippling mutations, rendering originally functional V gene rearrangements nonfunctional, were observed. Thus, the mutation pattern of rearranged Ig genes of HRS cells in lrcHL is clearly different from those in lymphocytic and histiocytic cells of lpHL, and resembles the pattern in HRS cells of cHL, suggesting that HRS cells in lrcHL derive from (preapoptotic) GC B cells that silenced hypermutation. In one case in addition to the dominant HRS cell clone, CD30(+) EBV-infected HRS-like cells unrelated to the tumor clone were observed, suggesting development of an expanded population of EBV-harboring HRS-like cells in the microenvironment of HL.

Arguello M, Sgarbanti M, Hernandez E, et al.
Disruption of the B-cell specific transcriptional program in HHV-8 associated primary effusion lymphoma cell lines.
Oncogene. 2003; 22(7):964-73 [PubMed] Related Publications
Primary effusion lymphoma (PEL) is a lymphoproliferative disease of B-cell origin that is associated with HHV-8 infection. PEL cells harbor a non-B, non-T phenotype and lack significant surface immunoglobulin (Ig) expression, a characteristic that has not been fully explained. In the present study, we demonstrate that PEL cells constitutively express interferon regulatory factor (IRF)-4, a transcription factor that regulates the activity of the immunoglobulin light-chain enhancer elements lambdaB and kappaE3' through binding to a composite Ets-IRF site. IRF-4 activity requires its physical interaction with PU.1, an Ets family member involved in the activation of genes essential for B-cell development. However, in PEL-derived B-cell lines, PU.1 expression was completely abrogated; expression of the B cell specific transcription factor Oct-2, which is known to regulate PU.1 expression, was also abolished. Moreover, the B-cell-specific coactivator of octamer factors, BOB-1/OcaB, was expressed at very decreased levels in PEL cells. Ectopic expression of Oct-2 was able to fully restore PU.1 promoter activity in the PEL cell line BCBL-1, while PU.1 expression also reconstituted the activity of the lambdaB Ets-IRF site. In addition, protein levels of BSAP/Pax-5 and IRF-8/ICSBP were undetectable in PEL cells. The pattern of transcription factor ablation observed in PEL was found to be comparable to that observed in classical Hodgkin's disease-derived cell lines, which also lack B-cell-specific surface markers. These observations indicate that disruption of the B-cell-specific transcriptional program is likely to contribute to the incomplete B-cell phenotype characteristic of PEL cells.

Pileri SA, Gaidano G, Zinzani PL, et al.
Primary mediastinal B-cell lymphoma: high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, BOB.1, and PU.1 in the absence of immunoglobulins.
Am J Pathol. 2003; 162(1):243-53 [PubMed] Free Access to Full Article Related Publications
Although primary mediastinal (thymic) large B-cell lymphoma has been primarily studied, its precise phenotype, molecular characteristics, and histogenesis are still a matter of debate. The International Extranodal Lymphoma Study Group collected 137 such cases for extensive pathological review. Histologically, the lymphomatous growth was predominantly diffuse with fibrosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. On immunohistochemistry, the following phenotype was observed: CD45(+), CD20(+), CD79a(+), PAX5/BSAP(+), BOB.1(+), Oct-2(+), PU.1(+), Bcl-2(+), CD30(+), HLA-DR(+), MAL protein(+/-), Bcl-6(+/-), MUM1/IRF4(+/-), CD10(-/+), CD21(-), CD15(-), CD138(-), CD68(-), and CD3(-). Immunoglobulins were negative both at immunohistochemistry and in situ hybridization. Molecular analysis, performed in 45 cases, showed novel findings. More than half of the cases displayed BCL-6 gene mutations, which usually occurred along with functioning somatic IgV(H) gene mutations and Bcl-6 and/or MUM1/IRF4 expression. The present study supports the concept that a sizable fraction of cases of this lymphoma are from activated germinal center or postgerminal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective immunoglobulin production despite the expression of OCT-2, BOB.1, and PU.1 transcription factors and the lack of IgV(H) gene crippling mutations.

Hertel CB, Zhou XG, Hamilton-Dutoit SJ, Junker S
Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma.
Oncogene. 2002; 21(32):4908-20 [PubMed] Related Publications
In classical Hodgkin lymphoma the malignant Hodgkin/Reed-Sternberg (HRS) cells characteristically constitute only a small minority of the tumour load. Their origin has been debated for decades, but on the basis of rearrangement and somatic hypermutations of their immunoglubulin (Ig) genes, HRS cells are now ascribed to the B-cell lineage. Nevertheless, phenotypically HRS cells have lost their B cell identity: they usually lack common B cell-specific surface markers such as CD19 and CD79a as well as Ig gene transcripts. Here we demonstrate that Ig promoters as well as both intronic and 3' enhancer sequences are transcriptionally inactive in HRS cell lines. This inactivity correlates with either reduced levels or even a complete lack of several B cell-specific transcription factors required for their expression: Oct-2, OBF-1, PU.1, E47/E12, PAX-5 and EBF. Moreover, we demonstrate that PU.1 and PAX-5 are significantly down-regulated in HRS cells in pathological specimens from primary tumour tissues. However, forced expression of these transcription factors can activate regulatory sequences of silenced B cell marker genes, and in one instance also transcription from a silenced endogenous locus. Thus, HRS cells are dedifferentiated B cells with global down-regulation of B cell-specific genes.

Jundt F, Kley K, Anagnostopoulos I, et al.
Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease.
Blood. 2002; 99(8):3060-2 [PubMed] Related Publications
Immunoglobulin transcription is impaired in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD). We recently demonstrated that defective immunoglobulin promoter transcription correlates with the down-regulation of the B-cell transcription factors Oct2 and BOB.1/OBF.1. These results prompted us to investigate whether immunoglobulin enhancer activity is also impaired in HRS cells and whether as yet unidentified factors could be necessary for immunoglobulin enhancer activity in HRS cells of cHD. Here we analyzed 30 cases of cHD for expression of the Ets family member PU.1 that is known to collaborate with multiple transcription factors and to regulate expression of immunoglobulin genes. We show that PU.1 is not expressed in primary and cultured HRS cells. Reintroduction of PU.1 and Oct2 in cultured HRS cells restored the activity of cotransduced immunoglobulin enhancer constructs. Our study identifies PU.1 deficiency as a recurrent defect in HRS cells that might contribute to their impairment of immunoglobulin transcription.

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