Histone deacetylase 1 and 2 in mesenchymal tumors

Pacheco, Marina; Nielsen, Torsten O.

doi:10.1038/modpathol.2011.157

Cited by 34 publications

(24 citation statements)

References 37 publications

(35 reference statements)

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“…HDAC-2 was the only one showing moderate to strong expression in all three cell lines, thereby making this a potential target for treatment. 61 HDAC-1 and −3 were moderately expressed in 2 out of 3 cell lines. A recent phase II trial with a pan-HDAC inhibitor SB939 as a single agent tested in 22 translocation associated sarcoma patients (5 of whom had MLS) revealed no objective responses but 2 out of 4 evaluable MLS patients achieved stable disease.…”

Section: Discussionmentioning

confidence: 95%

“…A recent phase II trial with a pan-HDAC inhibitor SB939 as a single agent tested in 22 translocation associated sarcoma patients (5 of whom had MLS) revealed no objective responses but 2 out of 4 evaluable MLS patients achieved stable disease. 62 Those patients with high HDAC-2 expression appeared to benefit the most; 61–63 however extensive pre-clinical selection of the most promising HDAC-inhibitors might be worthwhile in specific soft tissue sarcoma subtypes. DL-221, similar to the other two cell lines displays sensitivity to the commonly used chemotherapeutic doxorubicin; we are in the process of performing a high throughput drug screen to look for activity with novel targeted agents.…”

Section: Discussionmentioning

confidence: 99%

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Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

Graaff

Beird

et al. 2016

Laboratory Investigation

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Myxoid liposarcoma has the pathognomonic fusion oncogene FUS-DDIT3 encoding a chimeric transcription factor. Metastatic risk is higher with an increased round cell component and has been linked to aberrations involving the IGFR/PI3K/AKT pathway. These molecular insights have yet to translate to targeted therapies and the lack of experimental models is a major hindrance. We describe the initial in-depth characterization of a new cell line (DL-221) and establishment of a mouse xenograft model. The cell line DL-221 was derived from a metastatic pleural lesion showing myxoid and round cell histology. This newly established cell line was characterized for phenotypic properties and molecular cytogenetic profile, using PCR, COBRA-FISH and western blot. Next-generation whole exome sequencing was performed to further characterize the cell line and the parent tumor. NOD-SCID-IL2R gamma knockout mice were xenograft hosts. DL-221 cells grew an adhering monolayer and COBRA-FISH showed an aneuploid karyotype with t(12;16)(q13;p11) and several other rearrangements; RT-PCR demonstrated a FUS-DDIT3 fusion transcript type 1. Both the cell line and the original tumor harbored a TP53 compound heterozygous mutation in exon 4 and 7 and were wild type for PIK3CA. Moreover, among the 1254 variants called by whole exome sequencing, there was 77% concordance between the cell line and parent tumor. The recently described hotspot mutation in the TERT promoter region in myxoid liposarcomas was also found at C228T in DL-221. Xenografts suitable for additional pre-clinical studies were successfully established in mice after subcutaneous injection. The established DL-221 cell line is the only published available myxoid liposarcoma cell line that underwent spontaneous immortalization, without requiring SV40 transformation. The cell line and its xenograft model are unique and helpful tools to study the biology and novel potential targeted treatment approaches for myxoid liposarcoma.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

Graaff

Beird

et al. 2016

Laboratory Investigation

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“…Each tissue microarray contains duplicate, triplicate, or quadruplicate 0.6 mm (UBC, LUMC), 1.5 mm (LUMC), or 2.0 mm (MDACC, LUMC) cores derived from representative viable diagnostic areas identified by a specialized bone and soft tissue tumor pathologist (TON, AJL, JVMGB). Tissue microarrays from UBC included in this study are TMA 01-003, 10 TMA 03-008, 11 TMA 06-007, 12 TMA 06-001B, 13 TMAs 08-019, 09-006, 10-009, 14 TMAs 12-004, 12-005, 12-006, 12-010, 15 and TMA MPNST. 16 From MDACC, myxoid liposarcoma tissue microarrays contained untreated tumors and tumors pre-treated with chemotherapy, radiation, or a combination of both.…”

Section: Tumor Samples and Tissue Microarraysmentioning

confidence: 99%

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

et al. 2015

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New York esophageal squamous cell carcinoma 1 (NY-ESO-1, CTAG1B) is a cancer-testis antigen and currently a focus of several targeted immunotherapeutic strategies. We performed a large-scale immunohistochemical expression study of NY-ESO-1 using tissue microarrays of mesenchymal tumors from three institutions in an international collaboration. A total of 1132 intermediate and malignant and 175 benign mesenchymal lesions were enrolled in this study. Immunohistochemical staining was performed on tissue microarrays using a monoclonal antibody for NY-ESO-1. Among mesenchymal tumors, myxoid liposarcomas showed the highest positivity for NY-ESO-1 (88%), followed by synovial sarcomas (49%), myxofibrosarcomas (35%), and conventional chondrosarcomas (28%). Positivity of NY-ESO-1 in the remaining mesenchymal tumors was consistently low, and no immunoreactivity was observed in benign mesenchymal lesions. On the basis of these findings, nearly 90% of myxoid liposarcomas, as well as a significant proportion of synovial sarcomas, myxofibrosarcomas, and conventional chondrosarcomas are good candidates for immunotherapy targeting NY-ESO-1. Modern Pathology (2015) 28, 587-595; doi:10.1038/modpathol.2014.155; published online 21 November 2014New York esophageal squamous cell carcinoma 1 (NY-ESO-1), encoded by the CTAG1B gene, is a cancer-testis antigen that was identified in 1997 from the serum of a patient with esophageal squamous cell carcinoma. 1 Cancer-testis antigens such as NY-ESO-1 have attracted increasing attention as immunotherapeutic targets because, among normal tissues, they are expressed only in adult testis germ cells and are atypically re-expressed in many malignancies. 2,3 NY-ESO-1 is of particular interest to researchers and clinicians because it is highly immunogenic and is expressed in a variety of carcinomas, melanomas, and sarcomas. 4 A recent clinical trial of adoptive immunotherapy, using genetically modified T cells directed against NY-ESO-1, demonstrated objective clinical responses in a number of metastatic synovial sarcoma and melanoma patients with NY-ESO-1-positive tumors. 5 The results of that clinical trial highlight the potential effectiveness of immunotherapy against tumors expressing NY-ESO-1, and several clinical trials (using antigen sensitization, adoptive T-cell transfer, and dendritic cell vaccine strategies) are currently underway.Mesenchymal tumors arising from bone or soft tissues comprise many histologic subtypes, which even when taken together occur at a much lower rate than the more common carcinomas, creating a practical barrier to developing new drug therapies. However, the well-defined biology of many sarcomas suggests they may be particularly susceptible to appropriate targeted strategies. Recent studies have reported NY-ESO-1 expression in an especially large proportion of myxoid liposarcomas and synovial sarcomas. 2,6-9 These studies also revealed the

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“…To assess the immunohistochemical labeling of EZH2, we modified the scoring system described by Pacheo et al 18 The intensity of the nuclear staining was evaluated as follow: score 0: no visible staining; score 1: weak; score 2: moderate; score 3: intense. To evaluate the extension of the positive cells was based on the percentage of the cell with positive nuclear stain against the background (score 0: no visible staining; score 1: 1-50%; score 2: 51-75%; score 3: above 75%).…”

Section: Immunohistochemistrymentioning

confidence: 99%

SMARCB1 protein and mRNA loss is not caused by promoter and histone hypermethylation in epithelioid sarcoma

et al. 2013

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About 10% of epithelioid sarcomas have biallelic mutation of the SMARCB1 (SWI/SNF-related, matrixassociated, actin-dependent regulator of chromatin, subfamily b, member 1) gene resulting in a lack of this nuclear protein. It has been suggested that SMARCB1 may be silenced by epigenetic changes in the remaining 90% of tumors. Thus, we hypothesized that the promoter of SMARCB1 is hypermethylated. We also examined SMARCB1 mRNA level to determine if a post-translational change was possible. Thirty-six cases of epithelioid sarcomas were studied. Immunohistochemistry and mutation analysis of the SMARCB1 gene were performed to select appropriate cases. Methylation status was assessed by methylation-specific PCR. Laser capture microdissection of tumor cells followed by real-time PCR was applied to examine the expression of SMARCB1 mRNA. Of 36 epithelioid sarcomas, 31 (86%) displayed a lack of SMARCB1 nuclear protein. In all, 4 (13%) of 31 SMARCB1-negative cases harbored biallelic deletion while 9 (33%) cases showed single-allelic deletion. One (4%) frameshift deletion of exon 3 and one point mutation of exon 7 were also found. In 16 (59%) cases, both alleles were intact. Altogether, 25/31 (81%) SMARCB1-negative cases had at least one intact allele. None of these cases demonstrated promoter hypermethylation. Low levels of SMARCB1 mRNA were found in all cases with tumor tissue extracted RNA (because of the minimal normal cell contamination) but no mRNA could be detected in laser dissected cases (containing only tumor cells). Enhancer of zeste homolog 2 (EZH2) overexpression was not characteristic of epithelioid sarcoma. Thus, loss of SMARCB1 expression in epithelioid sarcoma is caused neither by DNA hypermethylation nor by post-translational modifications. Most likely it is the microRNA destruction of SMARCB1 mRNA but further investigations are needed to elucidate this issue. Keywords: epithelioid sarcoma; histone methylation; laser capture microdissection; methylation-specific PCR; promoter hypermethylation; SMARCB1The SMARCB1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1; also known as INI1, BAF47 and hSNF5) gene, located on chromosomal position 22q11.23, encodes a core subunit of the SWI/SNF ATP-dependent chromatin remodeling complex. 1 Such observations show these complexes regulate gene expression, at least in part, by inducing a nucleosome conformation that is more approachable to the transcriptional machinery. 2 Recently, inactivation of both alleles of the SMARCB1 gene was identified in the majority of malignant rhabdoid tumors, suggesting that loss-of-function mutations of the gene contributed to the oncogenesis of this type of tumor.

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Histone deacetylase 1 and 2 in mesenchymal tumors

Cited by 34 publications

References 37 publications

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

SMARCB1 protein and mRNA loss is not caused by promoter and histone hypermethylation in epithelioid sarcoma

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