Targeting EZH2 for the treatment of hepatosplenic T-cell lymphoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Pikman Y
PROVIDER: S-EPMC7160286 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
Publications
Targeting EZH2 for the treatment of hepatosplenic T-cell lymphoma.
Pikman Yana Y Conway Amy Saur AS Robichaud Amanda L AL Kitara Samuel S Church Alanna J AJ Kennedy Alyssa L AL Silverman Lewis B LB Billett Amy L AL Weinstock David M DM Harris Marian H MH Stegmaier Kimberly K
Blood advances 20200401 7
Similar Datasets
Project description: Not available
| S-EPMC6395348 | biostudies-literature
Project description:Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.
| S-EPMC5402251 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-05-24 | GSE57944 | GEO
Project description: Not available
| S-EPMC4648481 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-05-24 | E-GEOD-57944 | biostudies-arrayexpress
Project description:The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from ?? T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7?? and 2??) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal ?? T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents.
| S-EPMC3779008 | biostudies-literature
Project description:Hepatosplenic T-cell lymphoma is a rare form of T-cell lymphoma that predominantly emerges from neoplastic proliferation of cytotoxic T cells of γ/δ T-cell receptor-expressing lymphocytes. Isochromosome 7q and trisomy 8 are the most prevalent chromosomal abnormalities associated with hepatosplenic T-cell lymphoma, and most patients have mutations in genes related to chromatin remodeling or the JAK/STAT system. Hepatosplenic T-cell lymphoma can mimic various infectious diseases, immunological conditions, and other malignancies. Patients usually present with nonspecific constitutional symptoms and spleen and liver enlargement, with variable degrees of cytopenia. The rarity of this disease, coupled with the lack of lymph node involvement that is usually seen in lymphomas, causes significant difficulty in diagnosis, which inevitably delays the initiation of treatment. Managing this lymphoma is arduous because of its late presentation and aggressive nature, frequently resulting in rapid progression in its clinical course and refractoriness to conventional chemotherapy. There is a lack of international guidelines for its treatment, and in most cases, treatment is guided by case series. Here, we highlight the clinicopathological features and management of hepatosplenic T-cell lymphoma over a 10-year span in a single hematology referral center and review the literature.
| S-EPMC10625816 | biostudies-literature
Project description:We describe a case of unclassifiable T/NK-cell lymphoma with concomitant acute myeloid leukemia (AML). A 73-year-old Japanese man was diagnosed with AML by bone marrow smear, but the presence of splenomegaly and liver tumor was incompatible with AML. Splenectomy and hepatic resection were performed to resolve the thrombocytopenia and define the diagnosis. The pathological findings showed sinusoidal involvement of abnormal lymphoid cells that were CD3-positive but negative for T-cell receptor (TCR) rearrangement. Our case could not be categorized as hepatosplenic T-cell lymphoma because of the lack of immunohistological expression of TCR, despite the clinical similarity.
| S-EPMC9713219 | biostudies-literature
Project description: Not available
| S-EPMC10188490 | biostudies-literature
Project description:PurposeHepatosplenic T-cell lymphoma (HSTCL), mostly derived from γδ T cells, is a rare but very aggressive lymphoma with poor outcomes. In this study, we generated the first single cell landscape for this rare disease and characterized the molecular pathogenesis underlying the disease progression.MethodsWe performed paired single cell RNA-seq and T cell receptor (TCR) sequencing on biopsies from a HSTCL patient pre- and post- chemotherapy treatments. Following by a series of bioinformatics analysis, we investigated the gene expression profile of γδ HSTCS as well as its tumor microenvironment (TME).ResultsWe characterized the unique gene expressing signatures of malignant γδ T cells with a set of marker genes were newly identified in HSTCL (AREG, PLEKHA5, VCAM1 etc.). Although the malignant γδ T cells were expanded from a single TCR clonotype, they evolved into two transcriptionally distinct tumor subtypes during the disease progression. The Tumor_1 subtype was dominant in pre-treatment samples with highly aggressive phenotypes. While the Tumor_2 had relative mild cancer hallmark signatures but expressed genes associated with tumor survival signal and drug resistance (IL32, TOX2, AIF1, AKAP12, CD38 etc.), and eventually became the main tumor subtype post-treatment. We further dissected the tumor microenvironment and discovered the dynamically rewiring cell-cell interaction networks during the treatment. The tumor cells had reduced communications with the microenvironment post-treatment.ConclusionsOur study reveals heterogenous and dynamic tumor and microenvironment underlying pathogenesis of HSTCL and may contribute to identify novel targets for diagnosis and treatment of HSTCL in the future.
| S-EPMC9947078 | biostudies-literature