An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia

Cherian, Mathew; Olson, Sydney L.; Sundaramoorthi, Hemalatha; Cates, K. Lynn; Cheng, Xiaogang; Harding, John C. S.; Martens, Andrew; Challen, Grant A.; Tyagi, Manoj; Ratner, Lee; Rauch, Daniel A.

doi:10.1074/jbc.ra117.000164

Cited by 22 publications

(22 citation statements)

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“…Overexpression of IRF4 (WT) or IRF4 (K59R) in the bone marrow of host mice led to marked expansion of T lymphoid cells, but no alteration of B lymphoid or myeloid cell populations (Fig. 4 a) [ 18 ]. After 4 weeks, RNAseq was performed on GFP + CD45.2 + CD4 + CD8 − T-cells harvested from the thymus (3 mice for each condition).…”

Section: Resultsmentioning

confidence: 99%

“…In one study, knockdown of IRF4 resulted in up-regulation of Th1 transcription factors/cytokines including interferon (IFNγ) and interleukin 7 receptor (IL7R) [ 17 ]. We previously reported that the most common IRF4 mutation in ATLL, K59R, led to increased nuclear localization and transcriptional activity of IRF4, with increased expression of several IRF4-target genes, such as IL2, CCR4 , MYCN , and CTLA4 [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma

et al. 2020

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Background Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo. Results ATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo . To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo , transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and β, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2. Conclusions These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma

et al. 2020

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“…Importantly, IRF4 gene amplification and gain-of-function mutations frequently occur in ATL. 25,32,33 One gain-of-function mutation, K59R, has been shown to augment the transcriptional activity of IRF4. 33 Whether the genetic alterations in IRF4 collaborate with HBZ to promote senescence evasion, T-cell transformation, and ATL oncogenesis remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

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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“…Indeed, K59R mutation was reported to increase nuclear localization and transcriptional activation, resulting in the expansion of T-cells in vivo . 34 …”

Section: Association Of Genetic Alterations With Disease Phenotype Anmentioning

confidence: 99%

Clinical application of genomic aberrations in adult T-cell leukemia/lymphoma

Kataoka¹,

Koya²

2020

J Clin Exp Hematopathol

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Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell malignancy with a markedly poor prognosis. The low prevalence of ATL among human T-cell leukemia virus type-1 (HTLV-1) carriers and the long latency period before ATL onset suggest that additional genetic lesions are required for ATL leukemogenesis. Recently, a large-scale genetic analysis clarified the entire picture of genetic alterations, identified a number of novel driver genes, and delineated their characteristics. Frequent alterations are observed in the molecules belonging to T-cell receptor/NF-κB signaling and other T-cell-related pathways. A notable feature of the ATL genome is the predominance of gain-of-function alterations, including activating mutations in PLCG1 , PRKCB , and CARD11 . As many as one-fourth of all ATL cases harbor structural variations disrupting the 3′-untranslated region of the PD-L1 gene, leading to immune evasion of tumor cells. The frequency and pattern of these somatic alterations differ among clinical subtypes. Aggressive subtypes are associated with an increased burden of genetic alterations, and higher frequencies of TP53 and IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions than indolent subtypes. In contrast, STAT3 mutations are more characteristic of indolent ATL. Furthermore, these subtypes are further classified into molecularly distinct subsets with a different prognosis by genetic alterations. We present an overview of the current understanding of somatic alterations in ATL, with specific focus on their utility in clinical settings. Furthermore, we highlight their genetic features by exploring their similarities and differences among peripheral T-cell lymphomas.

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An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia

Cited by 22 publications

References 78 publications

Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma

Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma

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

Clinical application of genomic aberrations in adult T-cell leukemia/lymphoma

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