POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17

Zhao, Chen; Inoue, Jun; Imoto, Issei; Otsuki, Takemi; Iida, Shinsuke; Ueda, Ryuzo; Inazawa, Johji

doi:10.1038/sj.onc.1210637

Cited by 55 publications

(42 citation statements)

References 45 publications

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“…POU2AF1 protein, often called Oct-binding factor 1 (OBF-1), Oct coactivator from B cells (OCA-B), or BOB.1, is a transcriptional coactivator that is involved in transcription of immunoglobulin genes [25] and plays a role in B-cell development and Ig expression [26, 27]. Growth-promoting effects of overexpressed POU2AF1 have been demonstrated in human multiple myeloma cells from hematological malignancies [28]. In Hodgkin lymphoma, the percentage of relapsed patients after complete remission was greater in BOB.1-positive patients, and the association was stronger when BOB.1 expression was greater [29].…”

Section: Resultsmentioning

confidence: 99%

Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma

et al. 2016

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop resistant DLBCL; however, the genetic alterations in these patients are not well documented. To identify the genetic background of refractory DLBCL, we conducted whole-exome sequencing and transcriptome sequencing for six patients with refractory and seven with responsive DLBCL. The average numbers of pathogenic somatic single nucleotide variants and indels in coding regions were 71 in refractory patients (range 28–120) and 38 (range 19–66) in responsive patients. Missense mutations of TP53 were exclusive in 50% (3/6) of refractory patients and involved the DNA-binding domain of TP53. All missense mutations of TP53 were accompanied by copy number deletions. RAB11FIP5, PRKCB, PRDM15, FNBP4, AHR, CEP128, BRE, DHX16, MYO6, and NMT1 mutations were recurrent in refractory patients. MYD88, B2M, SORCS3, and WDFY3 mutations were more frequent in refractory patients than in responsive patients. REL–BCL11A fusion was found in two refractory patients; one had both fusion and copy number gain. Recurrent copy gains of POU2AF1, SLC1A4, REL11, FANCL, CACNA1D, TRRAP, and CUX1 with significantly increased average expression were found in refractory patients. The expression profile revealed enriched gene sets associated with treatment resistance, including oxidative phosphorylation and ATP-binding cassette transporters. In conclusion, this study integrated both genomic and transcriptomic alterations associated with refractory DLBCL and found several treatment-resistance alterations that may contribute to refractoriness.

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Section: Resultsmentioning

confidence: 99%

Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma

et al. 2016

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“…41 POU2AF1, a B-cell specific transcriptional co-activator associated with OCT1 and OCT2, is involved in the control of expansion and maintenance of mature B cells and promotes growth of MM plasma cells through the transactivation of BCMA. 42,43 The down-modulation of IGF-1, a molecule that has been implicated as an autocrine growth factor in MM, is also of note. 44,45 We also found modulation of several genes involved in TNF pathways, including CD40.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic anti-myeloma activity of ITF2357: inhibition of interleukin-6 receptor signaling and repression of miR-19a and miR-19b

et al. 2009

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The online version of this article has a supplementary appendix. BackgroundThe histone deacetylase inhibitor ITF2357 has potent cytotoxic activity in multiple myeloma in vitro and has entered clinical trials for this disease. Design and MethodsIn order to gain an overall view of the activity of ITF2357 and identify specific pathways that may be modulated by the drug, we performed gene expression profiling of the KMS18 multiple myeloma cell line treated with the drug. The modulation of several genes and their biological consequence were verified in a panel of multiple myeloma cell lines and cells freshly isolated from patients by using polymerase chain reaction analysis and western blotting. ResultsOut of 38,500 human genes, we identified 140 and 574 up-regulated genes and 102 and 556 down-modulated genes at 2 and 6 h, respectively, with a significant presence of genes related to transcription regulation at 2 h and to cell cycling and apoptosis at 6 h. Several of the identified genes are particularly relevant to the biology of multiple myeloma and it was confirmed that ITF2357 also modulated their encoded proteins in different multiple myeloma cell lines. In particular, ITF2357 down-modulated the interleukin-6 receptor α (CD126) transcript and protein in both cell lines and freshly isolated patients' cells, whereas it did not significantly modify interleukin-6 receptor β (CD130) expression. The decrease in CD126 expression was accompanied by decreased signaling by interleukin-6 receptor, as measured by STAT3 phosphorylation in the presence and absence of interleukin-6. Finally, the drug significantly down-modulated the MIRHG1 transcript and its associated microRNA, miR-19a and miR-19b, known to have oncogenic activity in multiple myeloma. ConclusionsITF2357 inhibits several signaling pathways involved in myeloma cell growth and survival.Key words: pleiotropic anti-myeloma, ITF2357, interleukin-6 receptor, miR-19a, miR-19b. -19a and miR-19b. Haematologica. 2010; 95:260-269. doi:10.3324/haematol.2009 This is an open-access paper.Pleiotropic anti-myeloma activity of ITF2357: inhibition of interleukin-6 receptor signaling and repression of miR-19a and miR-19b

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“…A large signature contains mature B-cell markers (CD19, CD22, CD72 and CD79B) and transcription factors important in B-cell development such as PAX5 and TCL1A. A second signature contains POU2AF1/OBF-1, together with its described targets: genes coding for immunoglobulin (IGHG1, IGHG3, IGHA1, IGHM, IGJ, IGKC and IGL) and the B-cell maturation factor, TNFRSF17/BCMA [18], [19]. The third B-cell signature contains cell surface markers found in immature B-cells (CD24, VPREB1, IGLL1/CD179B and CR2/CD21) in addition to transcription factors known to play a crucial role during early B-cell development (TCF3, SPIB and CUTL1).…”

Section: Resultsmentioning

confidence: 99%

TranscriptomeBrowser: A Powerful and Flexible Toolbox to Explore Productively the Transcriptional Landscape of the Gene Expression Omnibus Database

et al. 2008

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BackgroundAs public microarray repositories are constantly growing, we are facing the challenge of designing strategies to provide productive access to the available data.MethodologyWe used a modified version of the Markov clustering algorithm to systematically extract clusters of co-regulated genes from hundreds of microarray datasets stored in the Gene Expression Omnibus database (n = 1,484). This approach led to the definition of 18,250 transcriptional signatures (TS) that were tested for functional enrichment using the DAVID knowledgebase. Over-representation of functional terms was found in a large proportion of these TS (84%). We developed a JAVA application, TBrowser that comes with an open plug-in architecture and whose interface implements a highly sophisticated search engine supporting several Boolean operators (http://tagc.univ-mrs.fr/tbrowser/). User can search and analyze TS containing a list of identifiers (gene symbols or AffyIDs) or associated with a set of functional terms.Conclusions/SignificanceAs proof of principle, TBrowser was used to define breast cancer cell specific genes and to detect chromosomal abnormalities in tumors. Finally, taking advantage of our large collection of transcriptional signatures, we constructed a comprehensive map that summarizes gene-gene co-regulations observed through all the experiments performed on HGU133A Affymetrix platform. We provide evidences that this map can extend our knowledge of cellular signaling pathways.

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POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17

Cited by 55 publications

References 45 publications

Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma

Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma

Pleiotropic anti-myeloma activity of ITF2357: inhibition of interleukin-6 receptor signaling and repression of miR-19a and miR-19b

TranscriptomeBrowser: A Powerful and Flexible Toolbox to Explore Productively the Transcriptional Landscape of the Gene Expression Omnibus Database

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