Activation of Notch1 signaling by HTLV-1 Tax promotes proliferation of adult T-cell leukemia cells

Cheng, Wenzhao; Zheng, Tingjin; Wang, Yong; Cai, Kedan; Wu, Wencai; Zhao, Tiejun; Xu, Rui‐hua

doi:10.1016/j.bbrc.2019.03.094

Cited by 14 publications

(16 citation statements)

References 29 publications

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“…pcDNA3.1-HA-AHR was constructed by cloning human AHR cDNA with HA tag into pcDNA3.1(-) vector (Invitrogen). pCG-Tax and pcDNA3.1-Myc-His-HBZ were described previously [ 51 ]. 4xDRE-Luc was constructed by cloning four copies of DRE within human CYP1A1 promoter in front of a TATA box into pGL4.22 vector (Promega) [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

AHR is a tunable knob that controls HTLV-1 latency-reactivation switching

et al. 2020

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Establishing latent infection but retaining the capability to reactivate in certain circumstance is an ingenious tactic for retroviruses to persist in vivo while evading host immune surveillance. Many evidences indicate that Human T-cell leukemia virus type 1 (HTLV-1) is not completely silent in vivo . However, signals that trigger HTLV-1 latency-reactivation switching remain poorly understood. Here, we show that aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a critical role in HTLV-1 plus-strand expression. Importantly, HTLV-1 reactivation could be tunably manipulated by modulating the level of AHR ligands. Mechanistically, activated AHR binds to HTLV-1 LTR dioxin response element (DRE) site (CACGCATAT) and drives plus-strand transcription. On the other hand, persistent activation of nuclear factor kappa B (NF-κB) pathway constitutes one key prerequisite for AHR overexpression in HTLV-1 infected T-cells, setting the stage for the advent of AHR signaling. Our findings suggest that HTLV-1 might achieve its reactivation in vivo when encountering environmental, dietary, microbial and metabolic cues that induce sufficient AHR signaling.

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Section: Methodsmentioning

confidence: 99%

AHR is a tunable knob that controls HTLV-1 latency-reactivation switching

et al. 2020

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“…Thus, it is reasonable to speculate that the repression of miR-451 may be essential for ICN1-induced oncogenesis in HTLV-1 associated ATLL. Another hypothesis suggested by the results of Ansari et al [79] in glioblastoma cells is that the miR-451 level expression is dependent on glucose metabolism and is suppressed after AMP-activated protein kinase (AMPK) activation during glucose deprivation [77,80,81]. It is tempting to speculate that a similar mechanism may hold true for HTLV-1 associated ATLL since both AMPK and glucose levels have been implicated in ATLL progression.…”

Section: Discussionmentioning

confidence: 98%

“…A previous study provided evidence that expression of miR-451 in intracellular Notch1 (ICN1)-expressing bone marrow completely blocked the initiation of T cell acute lymphoblastic leukemia in recipient mice leaving normal T cell development and the generation of nonmalignant ICN1-overexpressing cells intact, indicating that reduced expression of these tumor suppressor genes was required for transformation [78]. Cheng et al [79] reported elevated expression of ICN1 in cell lines infected with HTLV-1 and that repression of cell proliferation and tumor formation in vitro and in vivo can be achieved by Knocking down ICN1 in ATL cells. The same study proposed that HTLV-1 promotes of growth of ATL cells by regulating Notch signaling through a posttranslational event that involves interactions of the viral tax protein with the Notch intracellular domain and the recombination signal binding protein immunoglobulin Jκ (RBP-jκ).…”

Section: Discussionmentioning

confidence: 99%

Global expression of noncoding RNome reveals dysregulation of small RNAs in patients with HTLV-1–associated adult T-cell leukemia: a pilot study

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et al. 2021

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Background: Adult T cell lymphoma/leukemia (ATLL) is a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus-1 (HTLV-1). Small RNAs (sRNAs), including microRNAs (miRNAs), play a pivotal role in the initiation and development of hematological malignancies and may represent potential therapeutic target molecules. However, little is known about how these molecules impact the pathogenesis of ATLL. In this study, we aimed to identify sRNA expression signatures associated with ATLL and to investigate their potential implication in the pathophysiology of the disease. Methods: Small-RNAseq analysis was performed in peripheral blood mononuclear cells from HTLV-1- associated ATLL (n = 10) in comparison to asymptomatic carriers (n = 8) and healthy controls (n = 5). Sequencing was carried out using the Illumina MiSeq platform, and the deregulation of selected miRNAs was validated by real-time PCR. Pathway analyses of most deregulated miRNA were performed and their global profiling was combined with transcriptome data in ATLL. Results: The sequencing identified specific sRNAs signatures associated with ATLL patients that target pathways relevant in ATLL, such as the transforming growth factor-(βTGF-β), Wnt, p53, apoptosis, and mitogen-activated protein kinase (MAPK) signaling cascades. Network analysis revealed several miRNAs regulating highly connected genes within the ATLL transcriptome. miR-451-3p was the most downregulated miRNA in active patients. Conclusions: Our findings shed light on the expression of specific sRNAs in HTLV-1 associated ATLL, which may represent promising candidates as biomarkers that help monitor the disease activity.

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“…Identi cation of miR-451a signature in PBMCs from ATLL patients associated with HTLV-1 infection is a novel nding of our study and has the potential to be a selective biomarker for ATLL development. It has been reported that miR-451 is downregulated in cytogenetically normal acute myeloid leukemia patients [70], and miR-451 functions as either a tumor suppressor [71,72] or an oncogene [73,74] [76] in glioblastoma cells is that the miR-451 level expression is dependent on glucose metabolism and found to be suppressed after AMP-activated protein kinase (AMPK) activation during glucose deprivation [74,77,78]. It is tempting to speculate that a similar mechanism may hold true for HTLV-1 associated ATLL since both AMPK and glucose levels have been implicated in ATLL progression.…”

Section: Discussionmentioning

confidence: 99%

Global expression of noncoding RNome reveals dysregulation of small RNAs in patients with HTLV-1–associated adult T-cell leukemia: a pilot study

Nacimento

Souza

Pessôa

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Adult T cell lymphoma/leukemia (ATLL) is a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus-1 (HTLV-1). Small RNAs (sRNAs), including microRNAs (miRNAs), play a pivotal role in the initiation and development of hematological malignancies and may represent potential therapeutic target molecules. However, little is known about how these molecules impact on the pathogenesis of ATLL. In this study, we aimed to identify sRNA expression signatures associated with ATLL and to investigate their potential implication in the pathophysiology of the disease. Methods Small-RNAseq analysis was performed in peripheral blood mononuclear cells from HTLV-1- associated ATLL (n = 10) in comparison to asymptomatic carriers (n = 8) and healthy controls (n = 5). Sequencing was carried out using the Illumina MiSeq platform, and the deregulation of selected miRNAs was validated by real-time PCR. Pathway analyses of most deregulated miRNA were performed and their global profiling was combined with transcriptome data in ATLL. Results The sequencing identified specific sRNAs signatures associated with ATLL patients that target pathways relevant in ATLL, such as TGF-β, Wnt, p53, apoptosis, and MAPK signaling cascades. Network analysis revealed several miRNAs regulating highly connected genes within the ATLL transcriptome. miR-451-3p was the most downregulated miRNA in active patients. Conclusions Our findings shed light on the expression of specific sRNAs in HTLV-1 associated ATLL, which may represent promising candidates as biomarkers that help monitor the disease activity.

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Activation of Notch1 signaling by HTLV-1 Tax promotes proliferation of adult T-cell leukemia cells

Cited by 14 publications

References 29 publications

AHR is a tunable knob that controls HTLV-1 latency-reactivation switching

AHR is a tunable knob that controls HTLV-1 latency-reactivation switching

Global expression of noncoding RNome reveals dysregulation of small RNAs in patients with HTLV-1–associated adult T-cell leukemia: a pilot study

Global expression of noncoding RNome reveals dysregulation of small RNAs in patients with HTLV-1–associated adult T-cell leukemia: a pilot study

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