Involvement of double-stranded RNA-dependent protein kinase and antisense viral RNA in the constitutive NFκB activation in adult T-cell leukemia/lymphoma cells

Kinpara, Shuichi; Ito, Sayaka; Takahata, Tatsuro; Saitoh, Yasunori; Hasegawa, Atsuhiko; Kijiyama, Mami; Utsunomiya, Atae; Masuda, Masato; Miyazaki, Yasushi; Matsuoka, Masao; Nakamura, Masataka; Shoji, Yasuhiro; Masuda, Tohru; Kannagi, Mari

doi:10.1038/leu.2015.1

Cited by 7 publications

(7 citation statements)

References 16 publications

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“…The oncogenic potential of HBZ has been established 2 , whereas the precise role of the new aberrant antisense transcripts remains unknown. An interesting clue is a recent report showing that antisense transcripts containing the LTR region induce NF-κB activation 46 .…”

Section: Discussionmentioning

confidence: 99%

Integrated molecular analysis of adult T cell leukemia/lymphoma

et al. 2015

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Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

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Section: Discussionmentioning

confidence: 99%

Integrated molecular analysis of adult T cell leukemia/lymphoma

et al. 2015

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“…It might reflect differences in the host responses. Since our previous study suggested that HTLV-1 provirus-encoded antisense RNAs at the LTR region potentially activate PKR, leading to NF-κB activation [ 32 ], it is conceivable that such anti-viral intrinsic mechanisms could influence IL-10 induction. Notably, polymorphisms in the promoter region of IL-10 are thought to be associated with various diseases, the outcome of both HCV [ 67 ] and HIV-1 [ 68 ] infection.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of genetic alterations in the mediators of T-cell receptor signaling pathway in ATL cells may partly be involved in the mechanisms of NF-κB activation [ 31 ]. In addition, our recent study indicated that ATL cells constitutively express antisense RNA including the HTLV-1 LTR region, resulting in constitutive activation of NF-κB through activation of the double-stranded RNA (dsRNA)-dependent protein kinase (PKR) [ 32 ]. This provided a new angle to understanding how HTLV-1 produces constitutive NF-κB activation without detectable Tax protein, once more indicating a link between HTLV-1 pathogenesis and innate host anti-viral immune responses.…”

Section: Introductionmentioning

confidence: 99%

IL-10-mediated signals act as a switch for lymphoproliferation in Human T-cell leukemia virus type-1 infection by activating the STAT3 and IRF4 pathways

et al. 2017

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Human T-cell leukemia virus type-1 (HTLV-1) causes two distinct diseases, adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since there are no disease-specific differences among HTLV-1 strains, the etiological mechanisms separating these respective lymphoproliferative and inflammatory diseases are not well understood. In this study, by using IL-2-dependent HTLV-1-infected T-cell lines (ILTs) established from patients with ATL and HAM/TSP, we demonstrate that the anti-inflammatory cytokine IL-10 and its downstream signals potentially act as a switch for proliferation in HTLV-1-infected cells. Among six ILTs used, ILTs derived from all three ATL patients grew much faster than those from three HAM/TSP patients. Although most of the ILTs tested produced IFN-γ and IL-6, the production of IL-10 was preferentially observed in the rapid-growing ILTs. Interestingly, treatment with exogenous IL-10 markedly enhanced proliferation of the slow-growing HAM/TSP-derived ILTs. The IL-10-mediated proliferation of these ILTs was associated with phosphorylation of STAT3 and induction of survivin and IRF4, all of which are characteristics of ATL cells. Knockdown of STAT3 reduced expression of IL-10, implying a positive-feedback regulation between STAT3 and IL-10. STAT3 knockdown also reduced survivin and IRF4 in the IL-10- producing or IL-10- treated ILTs. IRF4 knockdown further suppressed survivin expression and the cell growth in these ILTs. These findings indicate that the IL-10-mediated signals promote cell proliferation in HTLV-1-infected cells through the STAT3 and IRF4 pathways. Our results imply that, although HTLV-1 infection alone may not be sufficient for cell proliferation, IL-10 and its signaling pathways within the infected cell itself and/or its surrounding microenvironment may play a critical role in pushing HTLV-1-infected cells towards proliferation at the early stages of HTLV-1 leukemogenesis. This study provides useful information for understanding of disease mechanisms and disease-prophylactic strategies in HTLV-1 infection.

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“…In addition, similar spliced fusion transcripts are occasionally detected between HBZ and an exon of a highly expressed host gene adjacent to the proviral integration site. Given that a recent study shows that antisense transcripts containing the LTR region activate the NF‐κB pathway, these new aberrant fusion transcripts may contribute to the pathogenesis of ATL; however, their precise role remains to be determined.…”

Section: Htlv‐1 Integration and Their Genetic Abnormalitiesmentioning

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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Involvement of double-stranded RNA-dependent protein kinase and antisense viral RNA in the constitutive NFκB activation in adult T-cell leukemia/lymphoma cells

Cited by 7 publications

References 16 publications

Integrated molecular analysis of adult T cell leukemia/lymphoma

Integrated molecular analysis of adult T cell leukemia/lymphoma

IL-10-mediated signals act as a switch for lymphoproliferation in Human T-cell leukemia virus type-1 infection by activating the STAT3 and IRF4 pathways

Genetic alterations in adult T‐cell leukemia/lymphoma

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