PU.1 Regulates Positive Regulatory Domain I-Binding Factor 1/Blimp-1 Transcription in Lymphoma Cells

Desai, Shruti; Bolick, Sophia C.E.; Maurin, Michelle; Wright, Kenneth L.

doi:10.4049/jimmunol.0901120

Cited by 16 publications

(19 citation statements)

References 48 publications

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“…Chromatin preparation was performed as described by Desai, S. et al (28), adjusted for the number of cells for each immunoprecipitation and substituted with a concentration of 0.5mM EGTA for buffers containing this reagent. Briefly, 5×10 6 cells were treated for two hours with LBH589 12.5nM or DMSO control.…”

Section: Methodsmentioning

confidence: 99%

HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade

Woods

Sodré

Villagra

et al. 2015

Cancer Immunology Research

366

305

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Expression of PD-1 ligands by tumors and interaction with PD-1 expressing T cells in the tumor microenvironment can result in tolerance. Therapies targeting this co-inhibitory axis have proven clinically successful in the treatment of metastatic melanoma, non-small cell lung cancer and other malignancies. Therapeutic agents targeting the epigenetic regulatory family of histone deacetylases (HDACs) have shown clinical success in the treatment of some hematologic malignancies. Beyond direct tumor cell cytotoxicity, HDAC inhibitors have also been shown to alter the immunogenicity and enhance anti-tumor immune responses. Here we show that class I histone deacetylase inhibitors upregulated the expression of PD-L1 and, to a lesser degree, PD-L2 in melanomas. Evaluation of human and murine cell lines and patient tumors treated with a variety of HDAC inhibitors in vitro displayed upregulation of these ligands. This upregulation was robust and durable, with enhanced expression lasting past 96 hours. These results were validated in vivo in a B16F10 syngeneic murine model. Mechanistically, HDAC inhibitor treatment resulted in rapid upregulation of histone acetylation of the PD-L1 gene leading to enhanced and durable gene expression. The efficacy of combining HDAC inhibition with PD-1 blockade for treatment of melanoma was also explored in a murine B16F10 model. Mice receiving combination therapy had a slower tumor progression and increased survival compared to control and single agent treatments. These results highlight the ability of epigenetic modifiers to augment immunotherapies, providing a rationale for combining HDAC inhibitors with PD-1 blockade.

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Section: Methodsmentioning

confidence: 99%

HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade

Woods

Sodré

Villagra

et al. 2015

Cancer Immunology Research

366

305

View full text Add to dashboard Cite

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“…PRDM1 enriched chromatin was prepared from a total of 2×10 7 cells using 5 μg of PRDM1 (C14A4) rabbit mAb (Cell Signaling Technology, Beverly, MA) as described previously (39). ChIP-seq was done on the U266 cell line using chromatin from 2 ×10 8 cells.…”

Section: Methodsmentioning

confidence: 99%

“…pGL3-ELL3-Mut I & II was created through SacII-XhoI fragment subcloning from the single mutant constructs. Transfections and analysis were described previously and utilized 15 μg of promoter constructs, 5 μg of empty pcDNA3.1 or pcDNA3.1-HA-PRDM1α and 0.5 μg pRL-TK internal control construct (39, 42). The ELL3-expression plasmid was created from Raji cell cDNA, PCR amplified and cloned into pCR2.1.…”

Section: Methodsmentioning

confidence: 99%

Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Alexander

Watters

Reusch

et al. 2017

Molecular Immunology

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B cell activation is dependent on a large increase in transcriptional output followed by focused expression on secreted immunoglobulin as the cell transitions to an antibody producing plasma cell. The rapid transcriptional induction is facilitated by the release of poised RNA pol II into productive elongation through assembly of the super elongation complex (SEC). We report that a SEC component, the Eleven nineteen Lysine-rich leukemia (ELL) family member 3 (ELL3) is dynamically up-regulated in mature and activated human B cells followed by suppression as B cells transition to plasma cells in part mediated by the transcription repressor PRDM1. Burkitt’s lymphoma and a sub-set of Diffuse Large B cell lymphoma cell lines abundantly express ELL3. Depletion of ELL3 in the germinal center derived lymphomas results in severe disruption of DNA replication and cell division along with increased DNA damage and cell death. This restricted utilization and survival dependence reveal a key step in B cell activation and indicate a potential therapeutic target against B cell lymphoma’s with a germinal center origin.

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“…1,[21][22][23][24][25] Signals that can activate PRDM1 expression include those from cytokines (IL5, IL6, IL-10, and IL-21), toll-like receptors, and antigen receptors. AP-1, NF-B, IRF4/MUM1, STAT3, PU1, and C/EBP␤ induce PRDM1 transcription, while BCL6, PAX5, and BACH2 repress PRDM1 transcription.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

Nie

Zhang

Allawi

et al. 2010

The American Journal of Pathology

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PRDM1/Blimp-1, a master regulator for B cell terminal differentiation, is a putative tumor suppressor in diffuse large B cell lymphomas (DLBCL). Inactivating mutations of PRDM1 have been previously identified in a subset of nongerminal center B cell-like (GCB) DLBCL. We investigated the presence of alternative mechanisms of down-regulating PRDM1 in a cohort of 25 primary DLBCL and six DLBCL cell lines. While some DLBCL, predominantly the GCB-type, showed low levels of both PRDM1␣ mRNA and protein, presumably as a result of direct transcription repression, discordant expressions between the two were identified in a subset of DLBCL without PRDM1 mutations, the primarily non-GCB type, consistent with translational down-regulation. This subset of DLBCL exhibits relatively high PRDM1␣ mRNA levels but low levels of PRDM1. Data obtained from expression analysis , luciferase reporter assays , and transfection experiments support a role of targeting of PRDM1 by microRNA let-7 family in mediating this down-regulation. Let-7 , in particular let-7b , is overexpressed in DLBCL relative to normal GCB cells , suggesting that it is deregulated. Thus , abnormal epigenetic down-regulation of PRDM1 by let-7 and other microRNAs may represent an alternative mechanism of reducing normal PRDM1 function in a subset of DLBCL with relatively high PRDM1␣ mRNA expression and unmutated PRDM1. PRDM1/Blimp-1 is a master transcriptional regulator for terminal differentiation of B cells into plasma cells. [1][2][3][4] It also plays a critical role in effector and memory T-cell differentiation, 1,3,5 myeloid cell development, 6 dendritic cell development, 7 and epithelial cell differentiation. 8 Inactivating mutations that result in the generation of a severely truncated nonfunctional PRDM1 are found in about 20% of the diffuse large B cell lymphomas (DLBCLs) of the nongerminal center B cell (GCB) subtype 9,10 and also in about 19% of the primary DLBCL of the central nervous system. 11 These mutations are associated with deletion of the other paired PRDM1 allele at chromosome 6q21. These findings are consistent with PRDM1 being a DLBCL tumor suppressor gene and imply an important role of impairment of terminal B cell differentiation in DLBCL pathogenesis. However, many DLBCLs lack genetic alterations in PRDM1. Posttranscriptional down-regulation of PRDM1 in DLBCL has been suggested, but no systematic evaluation was performed. 10 In this study, we investigated this possibility in detail by comparative and quantitative analysis of PRDM1 mRNA and protein expression in different subgroups of DLBCL. We concluded that low or absent PRDM1 expression is a common phe-

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PU.1 Regulates Positive Regulatory Domain I-Binding Factor 1/Blimp-1 Transcription in Lymphoma Cells

Cited by 16 publications

References 48 publications

HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade

HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade

Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

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