scholarly journals Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3062-3071 ◽  
Author(s):  
Qian Zhang ◽  
HongYi Wang ◽  
Kanchan Kantekure ◽  
Jennifer C. Paterson ◽  
Xiaobin Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cell ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Transcriptional Activity ◽  
Cell Lymphoma ◽  
Cpg Island ◽  
Methylation Status ◽  
T Cell Lymphoma ◽  
Growth Promoting

Abstract Here we report that T-cell lymphoma cells carrying the NPM-ALK fusion protein (ALK+ TCL) frequently express the cell-stimulatory receptor ICOS. ICOS expression in ALK+ TCL is moderate and strictly dependent on the expression and enzymatic activity of NPM-ALK. NPM-ALK induces ICOS expression via STAT3, which triggers the transcriptional activity of the ICOS gene promoter. In addition, STAT3 suppresses the expression of miR-219 that, in turn, selectively inhibits ICOS expression. ALK+ TCL cell lines display extensive DNA methylation of the CpG island located within intron 1, the putative enhancer region, of the ICOS gene, whereas cutaneous T-cell lymphoma cell lines, which strongly express ICOS, show no methylation of the island. Treatment of the ALK+ TCL cell lines with DNA methyltransferase inhibitor reversed the CpG island methylation and augmented the expression of ICOS mRNA and protein. Stimulation of the ICOS receptor with anti-ICOS antibody or ICOS ligand-expressing B cells markedly enhanced proliferation of the ALK+ TCL cells. These results demonstrate that NPM-ALK, acting through STAT3 as the gene transcriptional activator, induces the expression of ICOS, a cell growth promoting receptor. These data also show that the DNA methylation status of the intronic CpG island affects transcriptional activity of the ICOS gene and, consequently, modulates the concentration of the expressed ICOS protein.

Genetic or Pharmacological Reductions in DNA Methylation Selectively Inhibit Peripheral T-Cell Lymphomagenesis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2760-2760
Author(s):  
Jennifer J. Trowbridge ◽  
Mingjie Li ◽  
Charles W.M. Roberts ◽  
Stuart H. Orkin
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Cell Lymphoma ◽  
Dna Demethylation ◽  
T Cell Lymphoma ◽  
Demethylating Agents ◽  
Dna Methylation Inhibitors

Abstract Abstract 2760 The significance of mutations in components of the DNA methylation machinery in blood cancer has become a topic of intense investigation. Unlike genetic modifications, the reversible nature of DNA methylation and other epigenetic changes makes them attractive therapeutic targets. Very recently, mutations in the DNA methyltransferase DNMT3A and the DNA demethylase TET2 were identified in human peripheral T cell lymphoma (PTCL) [1]. These findings provided a novel link between the development and progression of PTCL with deregulation of DNA methylation processes. Importantly, this finding also extended the few known mutations associated with both T-cell lymphoma and myeloid leukemia. Our previous work identified acute sensitivity of MLL-AF9–induced myeloid leukemia (AML) to DNA demethylation through loss or haploinsufficiency of the DNA methyltransferase Dnmt1 [2]. Here, we investigated the sensitivity of PTCL to DNA demethylation. Lymphoma was induced in mice by inactivation of Snf5, a core subunit of the SWI/SNF chromatin remodeling complex, driven by CD4Cre (CD4Cre-Snf52lox). Inactivation of Snf5 leads to rapid onset of mature CD8+ PTCL with a median survival of 10 weeks of age. Strikingly, loss of Dnmt1 in this model (CD4Cre-Snf52lox-Dnmt12lox) completely abrogated development of lymphoma. Furthermore, haploinsufficiency of Dnmt1 was sufficient to increase event-free survival to 13 weeks of age (p=0.0008). Loss or haploinsufficiency of Dnmt1 did not impact normal T cell development in the thymus with the exception of a modest reduction in CD8+ CD44hi memory T cells. Based on the selective response of PTCL to reduced levels of Dnmt1 and DNA methylation, we screened a panel of pharmacological DNA demethylating agents for efficacy in PTCL. We found three putative DNA methylation inhibitors; the nucleoside inhibitor zebularine and non-nucleoside inhibitors RG108 and procainamide, which inhibited proliferation of primary murine PTCL in vitro. These inhibitors were effective at doses that did not restrict the proliferation of normal CD8+ T cells. When these inhibitors were evaluated for efficacy in vivo, both zebularine and procainamide were found to inhibit growth of primary murine PTCL. Together, these results suggest that therapy of PTCL with DNA methylation inhibitors or other DNA demethylating agents may achieve a favorable therapeutic index. Further, these results support the concept of a shared competitive advantage of myeloid leukemia and T-cell lymphoma in carrying mutations in the DNA methylation machinery. [1] Couronne L et al., NEJM, 2012, 366:95-6; [2] Trowbridge et al., Genes Dev, 2012, 26:344-9. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Enhanced CXCR4 Expression Associates with Increased Gene Body 5-Hydroxymethylcytosine Modification but not Decreased Promoter Methylation in Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 539 ◽  
Author(s):  
Alexei J. Stuckel ◽  
Wei Zhang ◽  
Xu Zhang ◽  
Shuai Zeng ◽  
Urszula Dougherty ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Methylation Status ◽  
Cxcr4 Expression ◽  
Normal Colonic Mucosa ◽  
Gene Body ◽  
Expression Levels

In colorectal cancer (CRC), upregulation of the C-X-C motif chemokine receptor 4 (CXCR4) is correlated with metastasis and poor prognosis, highlighting the need to further elucidate CXCR4’s regulation in CRC. For the first time, DNA methylation and 5-hydroxymethylcytosine aberrations were investigated to better understand the epigenetic regulation of CXCR4 in CRC. CXCR4 expression levels were measured using qPCR and immunoblotting in normal colon tissues, primary colon cancer tissues and CRC cell lines. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. The DNA methylation status spanning CXCR4 gene was evaluated using combined bisulfite restriction analysis (COBRA). The methylation status in the CXCR4 gene body was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. CXCR4 expression levels were significantly increased in tumor stromal cells and in tumor colonocytes, compared to matched cell types from adjacent normal-appearing mucosa. CXCR4 promoter methylation was detected in a minority of colorectal tumors in the TCGA. The CpG island of the CXCR4 promoter showed increased methylation in three of four CRC cell lines. CXCR4 protein expression differences were also notable between microsatellite stable (MSS) and microsatellite instable (MSI) tumor cell lines. While differential methylation was not detected in CXCR4, enrichment of 5-hydroxymethylcytosine (5hmC) in CXCR4 gene bodies in CRC was observed compared to adjacent mucosa.

scholarly journals Curcumin Selectively Induces Apoptosis in Cutaneous T-Cell Lymphoma Cell Lines and Patients’ PBMCs: Potential Role for STAT-3 and NF-κB Signaling

2010 ◽  
Vol 130 (8) ◽  
pp. 2110-2119 ◽  
Author(s):  
Chunlei Zhang ◽  
Baoqiang Li ◽  
Xiang Zhang ◽  
Parul Hazarika ◽  
Bharat B. Aggarwal ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Potential Role ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoma Cell ◽  
Cutaneous T Cell Lymphoma

Anti-CD45 Mediated Cytolysis of Human T-Cell Lymphoma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4637-4637
Author(s):  
Gerald G. Wulf ◽  
Anita Boehnke ◽  
Bertram Glass ◽  
Lorenz Truemper
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cytolytic Activity ◽  
T Cell Lymphoma ◽  
Lymphoma Cell ◽  
Lymphoma Cells ◽  
Human T Cell

Abstract Anti-CD45 mediated cytoreduction is an effective means for T-cell depletion in rodents and humans. In man, the CD45-specific rat monoclonal antibodies YTH24 and YTH54 are IgG2b subclass, exert a predominantly complement-dependent cytolytic activity against normal T-lymphocytes, and have been safely given to patients as part of conditioning therapies for allogeneic stem cell transplantation. The efficacy of such antibodies against human lymphoma is unknown. Therefore, we evaluated the cytolytic activity of YTH24 and YTH54 by complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), as well as by direct apoptotic and antiproliferative effects, against a panel of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) cell lines, and against primary specimens. Significant CDC activity (>50% cytolysis) of the antibodies YTH54 and YTH24 was observed against three of five T-cell lymphoma lines, but against only one of nine B-cell lymphoma lines and none of four HD cell lines. The combination of YTH54 and YTH24 induced ADCC in all T-cell lymphoma cell lines and three primary leukemic T-cell lymphoma specimens, but were ineffective in B-cell lymphoma and HD cell lines.There were only minor effects of either antibody or the combination on lymphoma cell apoptosis or cell cycle arrest. In summary, anti-CD45 mediated CDC and ADCC via the antibodies YTH24 and YTH54 are primarily effective against lymphoma cells with T-cell phenotype, and may be an immunotherapeutic tool for the treatment of human T-cell lymphoma.

Methylation Profile of B-Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2951-2951
Author(s):  
Jun Fan ◽  
Asou Norio ◽  
Masao Matsuoka
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Cpg Island ◽  
Methylation Status ◽  
Lymphocytic Leukemia ◽  
Dna Hypomethylation ◽  
Peripheral Blood Mononuclear

Abstract DNA methylation plays an important role in the development and aging of mammalian cells, and its dysregulation has been frequently observed in cancer cells. The purpose of this study is to investigate the involvement of aberrant DNA methylation in B chronic lymphocytic leukemia (B-CLL) cells. We compared methylation status of B-CLL cells isolated from patients with that of normal CD19+ cells isolated from health donors by methylated CpG island amplification/representative difference analysis method. 5 hypermethylated and 27 hypomethylated DNA regions were identified in B-CLL sample. Among the 27 hypomethylated regions, 5 located on chromosome 9q34, 3 on 10q25-26 and 4 on 19q13. Methylation status was confirmed by sequencing using sodium bisulfite-treated DNA samples. By comparing DNA samples from same patients at different clinical stages, we found that lower methylation density in these regions is linked with disease progression. Expression of 15 genes surrounding hypomethylated regions was studied by RT-PCR. Expression of laminin beta3 gene and melanotransferrin gene was found to be upregulated in all B-CLL cell lines as well as lymphoma cell lines comparing with normal CD19+ peripheral blood mononuclear cells. B-cell CLL/lymphoma 11b gene showed increased expression in only 2 B-CLL cell lines. For other genes, no transcriptional change was found regardless of changed DNA methylation. This study showed the predominance of DNA hypomethylation in B-CLL cells compared with hypermethylation. Hypomethylated regions clustered in a limited number of chromosomes and methylation density appeared to be inversely correlated with disease progress. Figure Figure

Characterization of T-Cell Lymphoma Cell Lines with a Novel t(9;14)(q34;q11.2) Rearrangement: Does gamma-Secretase Inhibitor Sensitivity Depend on Intragenic NOTCH1 Breakpoint?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2332-2332
Author(s):  
Shinsuke Suzuki ◽  
Stefan Nagel ◽  
Bjoern Schneider ◽  
Maren Kaufmann ◽  
Dorothea Anders ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoma Cell ◽  
Gamma Secretase ◽  
Secretase Inhibitor ◽  
Gamma Secretase Inhibitor

Abstract Activating mutations and deletions affecting specific NOTCH1 protein domains have been recently shown to occur widely in T-cell neoplasia, e.g. in T-acute lymphoblastic leukemia (T-ALL). However, knowledge of NOTCH1 chromosomal alterations is largely based on a single cell line model (SUP-T1) with t(7;9)(q35;q34) in which NOTCH1 truncated at exon 24 is juxtaposed with TCRB. We describe the characterization of a novel rearrangement, t(9;14)(q34.3;q11) in two T-cell lymphoma cell lines, HD-MAR and HT-1. FISH analysis using fosmid clones and sequencing of fragments identified by long distance inverse PCR showed that in both cases t(9;14) effected tail-to-tail juxtaposition of intron 27 of NOTCH1 with TCRA genes, namely 5′-TRAV40 in HD-MAR, and intron 2 of TRAV5 in HT-1. Thus, in both cell lines t(9;14) places NOTCH1, truncated immediately 3′ of the HD-domain, under transcriptional control of TCRA. The 14q11.2 breakpoints in HD-MAR and HT-1 lie, respectively, near the proximal E-delta enhancer and amid a cryptic enhancer region represented by a cluster of T-cell specific DNase-I hypersensitive sites. Western blotting revealed prominent expression of truncated activated NOTCH1 polypeptides, ranging in size from 100 to 115 kDa in both cell lines. Antibodies recognizing ANK and TAD domains, believed essential for inducing T-ALL, detected the aberrant polypeptides. Moreover, treatment with gamma-secretase inhibitor (GSI) altered expression patterns of NOTCH1 polypeptides and induced growth inhibition due to G0/G1 cell cycle arrest in both t(9;14) cell lines, in stark contrast to GSI-resistant SUP-T1 cells wherein truncation occurs before the heterodimerization (HD) domain. (Another recently described t(7;9) cell line (CUTLL1) which is GSI-sensitive also carries a NOTCH1 breakpoint at intron 27.) The same protein species were not detectable by antibodies recognizing the transmembrane domain of NOTCH1 which requires GS for exposure suggesting nuclear access requires GS-cleavage. Immunostaining confirmed extranuclear blocking of NOTCH1 in response to GSI in HD-MAR/HT-1 but not in SUP-T1. In contrast, repression of HES1 occurred in response to GSI irrespective of NOTCH1 breakpoint location, suggesting its non-involvement in growth signaling. In addition to providing cell line models for a new NOTCH1 disease translocation, these data suggest that the sensitivities of T-cell neoplasias bearing NOTCH1 translocations may critically depend on whether 9q34 breakpoints lie upstream or downstream of the HD domain.

Sign in / Sign up

Export Citation Format

Share Document