PU.1 acts as tumor suppressor for myeloma cells through direct transcriptional repression of IRF4

Ueno, Niina; Nishimura, Nao; Ueno, Shikiko; Endo, Shinya; Tatetsu, Hiro; Hirata, Satoshi; Hata, Hiroyuki; Matsuoka, Masao; Mitsuya, Hiroaki; Okuno, Yutaka

doi:10.1038/onc.2017.79

Cited by 26 publications

(21 citation statements)

References 49 publications

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“…Both interferon (IFN) regulatory factors IRF8 and IRF4 bind PU.1 cooperatively at the IRF/PU.1 site in RAW264.7 cells [66]. PU.1 promotes macrophage differentiation toward alternatively activated macrophages and is involved in the development of many types of tumors including breast cancer [67], myeloma [68], acute myeloid leukemia [69], glioma [70] and hepatocellular carcinoma [71].…”

Section: Pu1mentioning

confidence: 99%

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Larionova

Kazakova

Patysheva

et al. 2020

Cancers

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Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

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Section: Pu1mentioning

confidence: 99%

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Larionova

Kazakova

Patysheva

et al. 2020

Cancers

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“…During PC differentiation however high concentrations of IRF4 promote binding to ISRE motifs, upregulating PC specific genes, like PDRM1, and inhibiting PU.Spib1)[12] [20]. In the majority of MM cells studied, PU.1 has been shown to be down regulated[66], however induced overexpression of PU.1 in MM cells causes down regulation of IRF4 expression and cell death by activation of the IRF7-INFβ pathway[67]. Up regulation of PU.1 could therefore represent a promising therapeutic strategy for MM.…”

mentioning

confidence: 99%

IRF4 in multiple myeloma—Biology, disease and therapeutic target

2018

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Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by abnormal proliferation of plasma cells. Interferon Regulatory Factor 4 (IRF4), a member of the interferon regulatory family of transcription factors, is central to the genesis of MM. IRF4 is highly expressed in B cells and plasma cells where it plays essential roles in controlling B cell to plasma cell differentiation and immunoglobulin class switching. Overexpression of IRF4 is found in MM patients' derived cells, often as a result of activating mutations or translocations, where it is required for their survival. In this review, we first describe the roles of IRF4 in B cells and plasma cells and then analyse the subversion of the IRF4 transcriptional network in MM. Moreover, we discuss current therapies for MM as well as direct targeting of IRF4 as a potential new therapeutic strategy.

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“…At the same time, several mutations in IRF4 DNA binding domain in primary CLL patients are associated with better prognosis [28]. [29,30]. Upregulation of PU.1 expression in HL and multiple myeloma cells lead to apoptosis of malignant B cells, moreover, higher PU.1 level is associated with better clinical outcome in FL patients, lower PU.1 level was observed in aggressive ABC DLBCL [29][30][31][32].…”

Section: Results and Disscutionmentioning

confidence: 99%

“…[29,30]. Upregulation of PU.1 expression in HL and multiple myeloma cells lead to apoptosis of malignant B cells, moreover, higher PU.1 level is associated with better clinical outcome in FL patients, lower PU.1 level was observed in aggressive ABC DLBCL [29][30][31][32]. CD38 and ZAP-70 double negative CLL cases are characterised by higher PU.1 mRNA expression that supposed to consider PU.1 expression as surrogate prognostic marker of favourable clinical outcome [29].…”

Section: Results and Disscutionmentioning

confidence: 99%

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Cd150 and Cd180 Are Involved in Regulation of Transcription Factors Expression in Chronic Lymphocytic Leukemia Cells

Gordiienko¹,

Shlapatska²,

Kholodniuk³

et al. 2017

Exp. Onc.

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Background: Sequential stages of B-cell development is stringently coordinated by transcription factors (TFs) network that include B-lineage commitment TFs (Ikaros, Runx1/Cbfb, E2A, and FOXO1), B-lineage maintenance TFs (EBF1 and PAX5) and stage specific set of TFs (IRF4, IRF8, BCL6, BLIMP1). Deregulation of TFs expression and activity is often occurs in malignant B cells. The aim of this study was to evaluate TFs expression in chronic lymphocytic leukemia cells taking into consideration CD150 cell surface expression. From other side we attempted to regulate TFs expression via CD150 and CD180 cell surface receptors. Materials and Methods: Studies were performed on normal peripheral blood B-cell subpopulations and chronic lymphocytic leukemia (CLL) cells isolated from peripheral blood of 67 primary untreated patients with CLL. Evaluation of TFs expression was performed on mRNA level using qRT-PCR and on protein level by western blot analysis. Results: Median of PAX5 and EBF1 mRNA expression was higher in cell surface CD150 positive (csCD150+) compared to csCD150- CLL cases or normal CD19+ and CD19+CD5+ B-cell subsets. Differences in mRNA expression of IRF8, IRF4 and BLIMP1 between studied groups of CLL and normal B cells were not revealed. All CLL cases were characterized by downregulated expression of PU.1 and BCL6 mRNAs in comparison to normal B cells. At the same time elevated SPIB mRNA expression level was restricted to CLL cells. Protein expression of IRF4, IRF8 and BCL6 was uniformly distributed between csCD150- and csCD150+ CLL cases. PU.1 protein and CD20 that is direct PU.1 target gene positively correlated with CD150 cell surface expression on CLL cells. Ligation of CD150 and CD180 alone or in combination upregulated IRF8 and PU.1 while downregulated the IRF4 mRNA expression. Signaling via CD150 or CD180 alone elevated the level of BCL6 mRNA. Strong downregulation of IRF4 mRNA was observed after CD150, CD180 or CD150 and CD180 coligation on CLL cells. We found that in CLL cells CD150 is a negative regulator of SPIB while CD180 is involved in upregulation of EBF1 expression level. Moreover, CD180 ligation on CLL cells caused increase of CD150 mRNA level that is a one of the EBF1 target genes. Conclusions: Analysis of TFs expression profile revealed upregulated SPIB mRNA level and downregulated PU.1 in CLL cells. CD150 and CD180 receptors may modulate transcriptional program in CLL cells by regulating the TFs expression levels.

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PU.1 acts as tumor suppressor for myeloma cells through direct transcriptional repression of IRF4

Cited by 26 publications

References 49 publications

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

IRF4 in multiple myeloma—Biology, disease and therapeutic target

Cd150 and Cd180 Are Involved in Regulation of Transcription Factors Expression in Chronic Lymphocytic Leukemia Cells

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