Targeted epigenetic repression of a lymphoma oncogene by sequence-specific histone modifiers induces apoptosis in DLBCL

Luo, Hong; Schmidt, Jennifer A.; Lee, Yi-Shan; Oltz, Eugene M.; Payton, Jacqueline E.

doi:10.1080/10428194.2016.1190973

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…Here we have identified significant differences in the histone acetylation of gene regulatory elements in samples from CTCL patients with HDACI-resistant versus -sensitive disease and linked them to significant expression changes in cell cycle, apoptosis, cytokine/chemokine signaling, and cell adhesion/migration pathways. We and others have previously shown that high levels of acetylation of enhancers and promoters can lead to overexpression of oncogenes that promote cancer pathogenesis [49,[59], [60], [61], [62]]. In this study, we demonstrated that enhancer elements near potential MF/SS oncogenes CCR6 , CXCR4 , and LAIR2 had significantly increased acetylation levels in HDACI-resistant samples also showed strong enhancer activity by luciferase reporter assay.…”

Section: Discussionsupporting

confidence: 60%

Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

et al. 2019

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Background Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. Methods Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. Findings Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR < 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5 , GSTM1 (redox); and CXCR4 , LAIR2 (cell adhesion/migration). Several of these, including LAIR2 , were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma ( n = 6), LAIR2 protein was also elevated ( p < 0·01) compared to controls. Interpretation This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. Funding NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842.

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Section: Discussionsupporting

confidence: 60%

Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

et al. 2019

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“…Fusion complexes of KRAB (Kruppel-associated box repressor) with dCas9 and zinc finger domains draw a diverse group of histone modifiers that cooperate to form heterochromatin. Targeting of the dCas9-KRAB and ZF-KRAB to distal regulatory elements effectively represses them and leads to silencing of the controlled genes (Thakore et al 2015;Chen et al 2014b, Luo et al 2017. A complex of dCas9 with methyltransferase 3A efficiently methylates promoter regions of targeted genes, decreasing their transcription (McDonald et al 2016).…”

Section: Gene Silencingmentioning

confidence: 99%

Emerging Gene Therapies for Genetic Hearing Loss

Ahmed

Shubina-Oleinik

Holt

2017

JARO

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Gene therapy, or the treatment of human disease using genetic material, for inner ear dysfunction is coming of age. Recent progress in developing gene therapy treatments for genetic hearing loss has demonstrated tantalizing proof-of-principle in animal models. While successful translation of this progress into treatments for humans awaits, there is growing interest from patients, scientists, clinicians, and industry. Nonetheless, it is clear that a number of hurdles remain, and expectations for total restoration of auditory function should remain tempered until these challenges have been overcome. Here, we review progress, prospects, and challenges for gene therapy in the inner ear. We focus on technical aspects, including routes of gene delivery to the inner ear, choice of vectors, promoters, inner ear targets, therapeutic strategies, preliminary success stories, and points to consider for translating of these successes to the clinic.

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“…[ 77 ] A distinct epigenetic modifier of BCL-6 with ZF-KRAB fusions repressed BCL-6 expression and led to cell death in DLBCL. [ 78 ] Subsequent investigation revealed that DNA methyltransferase azacitidine followed by R-CHOP proved feasible in a phase I trial of 12 high-risk patients with newly diagnosed DLBCL. [ 79 ] The efficacy of tazemetostat, a single-agent inhibitor of histone methyltransferase EZH2 for the treatment of rrDLBCL, was also evaluated in trials.…”

Section: Epigeneticsmentioning

confidence: 99%

R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms

Wang

2020

Chinese Medical Journal

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Although the first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (R-CHOP) substantially improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL), 40% of the patients suffered from relapsed/refractory disease and had poor survival outcomes. The detailed mechanism underlying R-CHOP resistance has not been well defined. For this review, we conducted a thorough search for literature and clinical trials involving DLBCL resistance. We discussed DLBCL biology, epigenetics, and aberrant signaling of the B-cell receptor ( BCR ), phosphatidylinositol 3-kinase ( PI3K ) /Akt , nuclear factor kappa light chain enhancer of activated B-cells ( NF-κB ), and the Janus kinase ( JAK )/signal transducer and activator of transcription 3 ( STAT3 ) pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance. The cell of origin, double- or triple-hit lymphoma and double-protein-expression, clonal evolution, tumor microenvironment, and multi-drug resistance help to contextualize DLBCL resistance in an (epi)genetically and biologically comparative manner. With better understanding of the biological and molecular landscape of DLBCL, a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.

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Targeted epigenetic repression of a lymphoma oncogene by sequence-specific histone modifiers induces apoptosis in DLBCL

Cited by 5 publications

References 38 publications

Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

Emerging Gene Therapies for Genetic Hearing Loss

R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms

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