Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma

Nakagawa, Masao; Shaffer, Arthur L.; Ceribelli, Michele; Zhang, Meili; Wright, George W.; Huang, Da Wei; Xiao, Wenming; Powell, John; Petrus, Michael; Yang, Yibin; Phelan, James D.; Kohlhammer, Holger; Dubois, Sigrid; Yoo, Hee Min; Bachy, Emmanuel; Webster, Daniel E.; Yang, Yandan; Xu, Weihong; Yu, Xin; Zhao, Hong; Bryant, Bonita R.; Shimono, Joji; Ishio, Takashi; Maeda, Masako; Green, Patrick L.; Waldmann, Thomas A.; Staudt, Louis M.

doi:10.1016/j.ccell.2018.06.014

Cited by 93 publications

(128 citation statements)

References 39 publications

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“…A recent study has shown that HBZ transactivates the basic leucine zipper ATF-like transcription factor 3, which forms a transcriptional complex with another transcription factor, interferon response factor 4 (IRF4), to promote ATL cell gene expression and proliferation. 27 Remarkably, the ablation of HBZ via CRISPR-Cas9 reduced the viability of ATL cells. 27 It is unclear whether the loss of cell viability is due to the senescence response associated with NF-kB hyperactivation.…”

Section: Discussionmentioning

confidence: 99%

“…27 Remarkably, the ablation of HBZ via CRISPR-Cas9 reduced the viability of ATL cells. 27 It is unclear whether the loss of cell viability is due to the senescence response associated with NF-kB hyperactivation. Importantly, IRF4 gene amplification and gain-of-function mutations frequently occur in ATL.…”

Section: Discussionmentioning

confidence: 99%

“…20 Importantly, ATL cells often constitutively express the HTLV-1 anti-sense mRNA-encoded bZIP protein, HBZ, [21][22][23][24][25] which antagonizes many functions of Tax and Rex 5,20 and promotes cell survival and proliferation. 26,27 In the absence of Tax expression, ATL cells evolve chronic Tax-independent NF-kB hyperactivation. 25 As such, we compared the state of NF-kB signaling in ATL cell lines with that in HTLV-1 2 T cells.…”

Section: Constitutive Nf-kb Activation and Cell-cycle Dysregulation Imentioning

confidence: 99%

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Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-κB hyperactivation–induced senescence

Shudofsky

Giam

2019

Blood Advances

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL). The HTLV-1 viral trans-activator/oncoprotein Tax is a major driver of ATL, yet it induces rapid p21Cip1/Waf1 (p21)- and p27Kip1-mediated cellular senescence through constitutive activation (hyperactivation) of NF-κB. Although constitutive NF-κB activation is a common feature of T/B-cell leukemia/lymphoma, including ATL, it is not known how ATL cells maintain chronic NF-κB activation without undergoing senescence. Here, we demonstrate that, in contrast to HTLV-1− T-cell lines, ATL cell lines no longer undergo Tax-induced senescence. Although Tax+ and Tax− ATL cell lines showed signatures of constitutive NF-κB activation, their ability to progress through the cell cycle was unaffected. In some cases, ATL cell lines continued to proliferate despite significant upregulation of p21; additionally, many cell lines displayed altered expression of G1 and G1/S cyclins, particularly overexpression of cyclin D2. We propose that, during the course of ATL development, leukemia cells acquire genetic/epigenetic changes that can mitigate the senescence response triggered by NF-κB hyperactivation. Restoring the NF-κB–induced senescence response would likely help to control the development and progression of ATL and similar lymphoid malignancies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Constitutive Nf-kb Activation and Cell-cycle Dysregulation Imentioning

confidence: 99%

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Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-κB hyperactivation–induced senescence

Shudofsky

Giam

2019

Blood Advances

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“…HBZ and HTLV-I-encoded TFs integrate into ATLL-specific BATF3 SE, further enhancing MYC expression by linking with BATF3/IRF4. Overexpressed MYC exacerbates disease through MYC seRNA transcription [68]. Interestingly, the nuclear matrix protein SAFA (also known as HNRNPU) displays an antiviral function by promoting immunity and stimulating productions of SE and seRNA of antiviral genes, including type I IFNs [69].…”

Section: Oncogenic Serna Formationmentioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

Tang

2020

Mol Cancer

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seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA's characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.

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“…UBE4B knockdown significantly impaired the expression of CD25 in Tax+ MT-2, HUT-102 and C8166 cell lines, but not in Tax-TL-OM1 cells ( Figure 4B, C). Expression of IRF-4, a transcription factor critical for the survival of ATLL cell lines [43], was significantly decreased in MT-2, but not in HUT-102, C8166 or TL-OM1 cells upon UBE4B depletion ( Figure 4B, C). Expression of cIAP-2, an anti-apoptotic NF-κB target gene, was significantly decreased in HUT-102, but not in MT-2, C8166 or TL-OM1 cells when UBE4B was knocked down ( Figure 4B).…”

Section: Knockdown Of Ube4b Impairs Tax-induced Expression Of Nf-κb Tmentioning

confidence: 99%

The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation

Harhaj

Mohanty²,

Han

et al. 2020

Preprint

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-κB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-κB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify novel Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax.Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by coimmunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-κB activation, whereas knockdown of UBE4B impaired Tax-induced NF-κB activation and the induction of NF-B target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48-and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-B activation. conjugation factor UBE4B as a novel Tax binding protein that promotes both K48-and K63-linked polyubiquitination of Tax. Knockdown or knockout of UBE4B impairs Taxinduced NF-B activation and triggers apoptosis of HTLV-1 transformed cells. Therefore, UBE4B is an integral host factor that supports HTLV-1 Tax polyubiquitination, NF-B activation and cell survival.

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Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma

Cited by 93 publications

References 39 publications

Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-κB hyperactivation–induced senescence

Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-κB hyperactivation–induced senescence

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation

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