Regulation of human T-cell leukemia virus type 1 antisense promoter by myocyte enhancer factor-2C in the context of adult T-cell leukemia and lymphoma.
Regulation of human T-cell leukemia virus type 1 antisense promoter by myocyte enhancer factor-2C in the context of adult T-cell leukemia and lymphoma.
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DOI：
10.3324/haematol.2021.279542
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发表时间：
2022-12-01
期刊：
影响因子：
10.1
通讯作者：
Jain, Pooja
中科院分区：
文献类型：
--
作者：
Madugula, Kiran K.;Joseph, Julie;DeMarino, Catherine;Ginwala, Rashida;Teixeira, Vanessa;Khan, Zafar K.;Sales, Dominic;Wilson, Sydney;Kashanchi, Fatah;Rushing, Amanda W.;Lemasson, Isabelle;Harhaj, Edward W.;Janakiram, Murali;Ye, Hilda;Jain, Pooja
成人T细胞白血病和淋巴瘤（ATLL）是由逆转录病毒，即人类T细胞白血病病毒1型（HTLV-1）引起的难治性T细胞瘤形成。患有ATLL的患者预后不良，并且缺乏治疗选择。与存在于5'启动子区长末端重复序列（LTR）的病毒反式激活蛋白Tax的零星表达相反，HTLV-1 bZIP基因（HBZ）由3' LTR（反义启动子）编码，并且在ATLL细胞和患者中保持其恒定表达。反义启动子与选择性逆转录病毒基因表达相关，并且一直是一种未充分研究的现象。在此，我们描述了转录因子MEF（肌细胞增强因子）-2家族成员的活性，这些成员被发现在3 'LTR富集，并在ATLL的发病机制中发挥重要作用。在四种MEF同种型（A至D）中，MEF-2A和2C在广泛的ATLL细胞系和急性ATLL患者中高度过表达。MEF-2同种型的活性通过敲低实验确定，敲低实验导致细胞增殖降低和细胞周期进程调节。在3 'LTR沿着观察到MEF-2C与辅因子Menin和JunD的高度富集，导致MEF-2C在该区域与HBZ结合。MEF-2蛋白的化学抑制导致体外ATLL细胞的细胞毒性和人源化小鼠模型中前病毒负荷的减少。综上所述，本研究提供了一种新的3 'LTR调控机制，并建立了MEF-2信号传导作为ATLL治疗干预的潜在靶点。
Adult T-cell leukemia and lymphoma (ATLL) is an intractable T-cell neoplasia caused by a retrovirus, namely human T-cell leukemia virus type 1 (HTLV-1). Patients suffering from ATLL present a poor prognosis and have a dearth of treatment options. In contrast to the sporadic expression of viral transactivator protein Tax present at the 5’ promoter region long terminal repeats (LTR), HTLV-1 bZIP gene (HBZ) is encoded by 3’LTR (the antisense promoter) and maintains its constant expression in ATLL cells and patients. The antisense promoter is associated with selective retroviral gene expression and has been an understudied phenomenon. Herein, we delineate the activity of transcription factor MEF (myocyte enhancer factor)-2 family members, which were found to be enriched at the 3'LTR and play an important role in the pathogenesis of ATLL. Of the four MEF isoforms (A to D), MEF-2A and 2C were highly overexpressed in a wide array of ATLL cell lines and in acute ATLL patients. The activity of MEF-2 isoforms were determined by knockdown experiments that led to decreased cell proliferation and regulated cell cycle progression. High enrichment of MEF-2C was observed at the 3'LTR along with cofactors Menin and JunD resulting in binding of MEF-2C to HBZ at this region. Chemical inhibition of MEF-2 proteins resulted in the cytotoxicity of ATLL cells in vitro and reduction of proviral load in a humanized mouse model. Taken together, this study provides a novel mechanism of 3’LTR regulation and establishes MEF-2 signaling a potential target for therapeutic intervention for ATLL.
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影响因子：
11.4
作者：
Marcais, Ambroise;Lhermitte, Ludovic;Hermine, Olivier
通讯作者：
Hermine, Olivier
影响因子：
4.5
作者：
Di Giorgio E;Franforte E;Cefalù S;Rossi S;Dei Tos AP;Brenca M;Polano M;Maestro R;Paluvai H;Picco R;Brancolini C
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