Polycomb-dependent epigenetic landscape in adult T-cell leukemia

Fujikawa, Dai; Nakagawa, Shota; Hori, Makoto; Kurokawa, Naoya; Soejima, Ai; Nakano, Kazumi; Yamochi, Tadanori; Nakashima, Makoto; Kobayashi, Seiichiro; Tanaka, Yuetsu; Iwanaga, Masako; Utsunomiya, Atae; Uchimaru, Kaoru; Yamagishi, Masaaki; Watanabe, Toshiki

doi:10.1182/blood-2015-08-662593

Cited by 128 publications

(142 citation statements)

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“…Interestingly, it was demonstrated that NFκB and PRC signaling pathways support each other via a positive feedback loop in numerous cancers (Dutton et al, 2007; Fujikawa et al, 2016; Iannetti et al, 2014; Lee et al, 2011; Mulero et al, 2013; Yamagishi et al, 2012) including glioblastoma (Jiang et al, 2013), providing a plausible explanation for miR-128 action as an NFκB antagonist due to its anti-PRC activity. It remains to be investigated whether the reciprocal inhibition of NFκB and miR-128 in glioblastoma cells is a direct mechanism.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells

et al. 2017

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Summary Large scale transcriptomic profiling of glioblastoma (GBM) into subtypes has provided remarkable insight about the pathobiology and heterogeneous nature of this disease. The mechanisms of speciation and inter-subtype transitions of these molecular subtypes require better characterization to facilitate the development of subtype-specific targeting strategies. The deregulation of microRNA expression among GBM subtypes, and their subtype-specific targeting mechanisms are poorly understood. To reveal the underlying basis of microRNA-driven complex subpopulation dynamics within the heterogeneous intra-tumoral ecosystem, we characterized the expression of subtype-enriched microRNA-128 (miR-128) in transcriptionally and phenotypically diverse subpopulations of patient-derived glioblastoma stem-like cells. As microRNAs are capable of re-arranging the molecular landscape in a cell type-specific manner, we argue that alterations in miR-128 levels are a potent mechanism of bidirectional transitions between GBM subpopulations resulting in intermediate hybrid stages and emphasizing highly intricate intra-tumoral networking.

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Section: Resultsmentioning

confidence: 99%

MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells

et al. 2017

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“…99 Integrative analyses of the epigenome (n 5 3) and transcriptome (n 5 58) of primary ATL cells revealed that PRC2 components, including EZH2, were highly expressed and that H3K27m3 was significantly and frequently reprogrammed in over half of the genes (53.8%). Furthermore, H3K27me3 pattern in ATL was distinct from that in other cancer types and PcG-dependent cell lineages.…”

Section: Abnormal Histone Modification Patternsmentioning

confidence: 99%

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Watanabe

2017

Blood

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Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

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“…This histone modification is usually accompanied by the loss of H3K4 methylation and is thought to be mediated by the aberrant upregulation of polycomb repressive complex (PRC) 2 proteins, such as EZH2, in ATL . One of the potential mechanisms involved in EZH2 overexpression in ATL is the constitutive activation of the NF‐κB pathway, in which NF‐κB/Rel proteins have been shown to directly control EZH2 transcription . Together with EZH2, its homologue EZH1 is also highly expressed and simultaneously contributes to increased levels of H3K27 methylation in ATL.…”

Section: Extensive Accumulation Of Repressive Histone Marks Caused Bymentioning

confidence: 99%

Genetic alterations in adult T‐cell leukemia/lymphoma

Kogure

Kataoka

2017

Cancer Science

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Adult T‐cell leukemia/lymphoma (ATL) is a peripheral T‐cell neoplasm with a dismal prognosis. It is caused by human T‐cell leukemia virus type‐1 (HTLV‐1) retrovirus. A long latency period from HTLV‐1 infection to ATL onset suggests that not only HTLV‐1 proteins, such as Tax and HBZ, but also additional genetic and/or epigenetic events are required for ATL development. Although many studies have demonstrated the biological functions of viral genes, alterations of cellular genes associated with ATL have not been fully investigated. Recently, a large‐scale integrated genetic analysis revealed the entire landscape of somatic aberrations in ATL. This neoplasm is characterized by frequent gain‐of‐function alterations in components of the T‐cell receptor/NF‐κB signaling pathway, including activating mutations in the PLCG1,PRKCB,CARD11 and VAV1 genes, and CTLA4‐CD28 and ICOS‐CD28 fusions. Importantly, molecules associated with immune surveillance, such as HLA‐A/B,CD58 and FAS, are affected recurrently. Among them, one notable lesion occurs as frequent structural variations that truncate the PD‐L1 3′‐untranslated region, leading to its overexpression. Other genetic targets include transcription factors (IRF4,IKZF2, and GATA3) and chemokine receptors (CCR4,CCR7 and GPR183), which are functionally relevant in normal T cells. A substantial proportion of ATL cases show widespread accumulation of repressive epigenetic changes, such as trimethylation of histone H3 lysine 27 and DNA hypermethylation of CpG islands, which coordinately modulate multiple pathways, including Cys2‐His2 zinc finger genes involved in silencing retroelements. Here we review the current understanding of the genetic/epigenetic aberrations in ATL, focusing on their relevance in its molecular pathogenesis.

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Polycomb-dependent epigenetic landscape in adult T-cell leukemia

Abstract: Key Points ATL involves genome-wide reprogramming of the H3K27me3 pattern that is distinct from other cell types. Druggable epigenetic mechanisms are associated with ATL cell development and HTLV-1–mediated transformation.

Cited by 128 publications

References 60 publications

MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells

MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Genetic alterations in adult T‐cell leukemia/lymphoma

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