HDAC Inhibitors Impair GATA-3 DNA Binding and Target Gene Expression in T-cell Neoplasms
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE219065 | GEO | 2023/01/31
REPOSITORIES: GEO
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Project description:Gene expression values were determined for HuT78 parental cells and cells selected with romidpesin in the presence of P-glycoprotein inhibitors. HuT78 DpVp35 cells are maintained in 35 ng/ml romidepsin with 2.5 µg/ml verapamil and HuT78 DpP100 cells are maintained in 100 ng/ml romidepsin with 1 µM valspodar To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein (Pgp) inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat and vorinostat. A custom Taqman array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased expression and a 4- to 8-fold increase in mitogen activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared to parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared to romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 Phase II study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials. Gene expression in resistant lines was compared to parental lines
2013-03-12 | E-GEOD-45018 | biostudies-arrayexpress
Project description:AHI-1 is an oncogene often targeted by provirus insertional mutagenesis in murine leukemias and lymphomas. Aberrant expression of human AHI-1 occurs in cutaneous T-cell lymphoma (CTCL) cells and in CD4+CD7- Sezary cells from patients with Sezary syndrome (SS). Stable knockdown of AHI-1 using retroviral-mediated RNA interference in CTCL cells inhibits their transforming activity in vitro and in vivo. To identify genes involved in AHI-1-mediated transformation, microarray analysis was performed to identify differentially expressed genes in AHI-1 suppressed CTCL cells. Fifteen up-regulated and six down-regulated genes were identified and confirmed by Q-RT-PCR. Seven were further confirmed in a microarray analysis of CD4+CD7- Sezary cells from SS patients. HCK and BIN1 emerged as new candidate cooperative genes, with differential protein expression which correlates with observed transcript changes. Interestingly, changes in HCK phosphorylation and biological response to its inhibitor, dasatinib, were observed in AHI-1 suppressed or overexpressed cells. The tumor suppressor BIN1 physically interacts with MYC in CTCL cells, which also exhibit differential MYC protein expression. In addition, aberrant expression of alternative splicing forms of BIN1 was observed in primary and transformed CTCL cells. These findings indicate that HCK and BIN1 may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells. Experiment Overall Design: Two groups, each with two subgroups, subgroups having 2 or 3 replicates each
2009-02-21 | E-GEOD-14746 | biostudies-arrayexpress
Project description:AHI-1 is an oncogene often targeted by provirus insertional mutagenesis in murine leukemias and lymphomas. Aberrant expression of human AHI-1 occurs in cutaneous T-cell lymphoma (CTCL) cells and in CD4+CD7- Sezary cells from patients with Sezary syndrome (SS). Stable knockdown of AHI-1 using retroviral-mediated RNA interference in CTCL cells inhibits their transforming activity in vitro and in vivo. To identify genes involved in AHI-1-mediated transformation, microarray analysis was performed to identify differentially expressed genes in AHI-1 suppressed CTCL cells. Fifteen up-regulated and six down-regulated genes were identified and confirmed by Q-RT-PCR. Seven were further confirmed in a microarray analysis of CD4+CD7- Sezary cells from SS patients. HCK and BIN1 emerged as new candidate cooperative genes, with differential protein expression which correlates with observed transcript changes. Interestingly, changes in HCK phosphorylation and biological response to its inhibitor, dasatinib, were observed in AHI-1 suppressed or overexpressed cells. The tumor suppressor BIN1 physically interacts with MYC in CTCL cells, which also exhibit differential MYC protein expression. In addition, aberrant expression of alternative splicing forms of BIN1 was observed in primary and transformed CTCL cells. These findings indicate that HCK and BIN1 may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells. Keywords: Cell type comparison
2009-02-07 | GSE14746 | GEO
Project description:Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.
2023-09-29 | GSE229406 | GEO
Project description:Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.
2023-09-29 | GSE227326 | GEO
Project description:Epigenetic changes deregulate gene expression to drive oncogenesis. The reversible nature of these changes enables therapeutic targeting, as in cutaneous T-cell lymphoma (MF/SS), Histone deacetylase inhibitors (HDACi), which alter epigenetic modifications, are effective in ~30% of MF/SS patients. However, there are no markers that predict MF/SS progression or therapy resistance. We hypothesized that epigenetic alterations drive MF/SS progression and promote HDACi drug resistance. Therefore, we profiled the epigenomes and transcriptomes of malignant T cell purified from skin biopsies and peripheral blood from MF/SS patients (N=21) before and after treatment with HDACi, as well as in vitro HDACi-treated CD4+ T cells from healthy donors. Here we report for the first time the epigenome-wide map of acetylation changes in MF/SS patients treated with HDACi, and define the significant differences in regulatory element activity and corresponding transcriptional changes in HDACi-sensitive versus resistant tumors. Our studies identified genes not previously associated with MF/SS, nor with disease progression or HDACi resistance, and were enriched in pathways that regulate apoptosis (BIRC5), cell cycle (RRM2), and chromosome cohesion (CENPH). We also identified a striking number of genes whose products are involved in cell adhesion and migration, including CCR6, LAIR2, VCAM1, and EPCAM. The mRNA of LAIR2, which encodes a receptor protein secreted by activated T cells that binds collagen and prevents binding of the inhibitory receptor LAIR1, was significantly upregulated in MF/SS tumors that were resistant to HDACi therapy and manifested in both skin and peripheral blood. We also detected elevated levels of LAIR2 protein in the plasma of MF/SS patients with progressive disease. Taken together, these studies defined the first epigenome-wide acetylation landscape of HDACi responsive and resistant MF/SS tumors, identified significantly altered patterns of epigenetic regulation and corresponding gene expression in HDACi resistant MF/SS tumors, and connected them to novel pathways of disease progression, particularly in cell adhesion and migration. These findings may represent novel predictive markers for MF/SS progression that are also targets for future therapeutic development.
2019-08-09 | GSE132053 | GEO
Project description:Various types of HDAC inhibitor are now planned or on going to use against non-Hodgkin’s lymphoma including CTCL. However there is a lack of molecular based evidence not only for which HDACi might be effective to use against advanced CTCL but also for which genes might be pivotal target gene(s) of HDACi. To investigate expression changes of miRNAs by HDACis, we conducted miRNA microarray by using CTCL cell lines.
2016-05-07 | GSE81190 | GEO
Project description:We demonstrate that the combination of the HDAC inhibitor, romidepsin, and the demethylating agent, azacitidine, exerts synergistic anti-proliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines as well as CD4+ T cells derived from patients with Sézary Syndrome (SS) with high tumor burden. We identified genes that were selectively induced by the combination treatment, such the tumor suppressor gene RhoB. We performed global CpG methylation-sequencing in a CTCL cell line and in patient cells. Results showed a subset of genes with a unique change in methylation profile in the combination treatment as compared to single drugs.
2016-03-30 | E-GEOD-66732 | biostudies-arrayexpress
Project description:Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by Assay of Transposase-Accessible Chromatin (ATAC-seq). Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic vs. non-leukemic (host) CD4+ T cells in CTCL patients, vs. CD4+ T cells in healthy donors. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4+ T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.
2017-04-20 | GSE85853 | GEO
Project description:Gene expression values were determined for HuT78 parental cells and cells selected with romidpesin in the presence of P-glycoprotein inhibitors. HuT78 DpVp35 cells are maintained in 35 ng/ml romidepsin with 2.5 µg/ml verapamil and HuT78 DpP100 cells are maintained in 100 ng/ml romidepsin with 1 µM valspodar To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein (Pgp) inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat and vorinostat. A custom Taqman array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased expression and a 4- to 8-fold increase in mitogen activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared to parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared to romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 Phase II study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials.
2013-03-12 | GSE45018 | GEO