Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis using the new oral demethylating agent OR-2100.
Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis using the new oral demethylating agent OR-2100.
复制标题
使用新型口服去甲基化剂 OR-2100 将异常 DNA 高甲基化作为 ATL 白血病发生的驱动因素。
作者：
Tatsuro Watanabe;S. Yamashita;H. Ureshino;K. Kamachi;Y. Kurahashi;Y. Fukuda;N. Yoshida;Naoko Hattori;Hideaki Nakamura;A. Sato;A. Kawaguchi;N. Sueoka;K. Kojima;S. Okada;T. Ushijima;S. Kimura;E. Sueoka
成人T细胞白血病-淋巴瘤（ATL）是由人T细胞嗜淋巴细胞病毒-1（HTLV-1）转化的CD 4 + T细胞的侵袭性血液恶性肿瘤。大多数HTLV-1感染者无症状，只有3-5%的携带者发展为ATL。在这里，我们描述了异常DNA甲基化对ATL白血病发生的贡献。基于CADM 1和CD 7表达状态分别分离HTLV-1感染的T细胞及其未感染的对应物，并通过全基因组DNA甲基化谱鉴定HTLV感染的T细胞特异性的差异甲基化位置（DMP）。DNA甲基化在高甲基化DMPs上的积累与ATL的发生和进展密切相关。此外，我们确定了22个基因下调由于启动子高甲基化在HTLV-1感染的T细胞，包括THEMIS，LAIR 1和RNF 130，负调节T细胞受体（TCR）信号。TCR信号转导子ZAP-70的磷酸化在HTLV-1感染的细胞系中失调，但通过THEMIS的重新表达而正常化。因此，我们假设DNA超甲基化有助于在ATL白血病发生过程中HTLV-1感染细胞的生长优势。为了测试这个想法，我们研究了具有增强的口服生物利用度的新型地西他滨（DAC）前药OR-1200和OR-2100（OR 21）的抗ATL活性。DAC和OR 21均抑制通过植入HTLV-1感染的细胞建立的异种移植肿瘤中的细胞生长，伴随着整体DNA低甲基化。OR 21的血液毒性低于DAC，而两种化合物之间的肿瘤生长抑制几乎相同，使其适用于ATL患者来源的异种移植小鼠的长期治疗。我们的研究结果表明，区域DNA超甲基化在ATL白血病的发生和有效的治疗靶点的功能是重要的。
Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy of CD4+ T-cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Most HTLV-1-infected individuals are asymptomatic and only 3-5% of carriers develop ATL. Here, we describe the contribution of aberrant DNA methylation to ATL leukemogenesis. HTLV-1-infected T-cells and their uninfected counterparts were separately isolated based on CADM1 and CD7 expression status, and differentially methylated positions (DMPs) specific to HTLV-infected T-cells were identified through genome-wide DNA methylation profiling. Accumulation of DNA methylation at hypermethylated DMPs correlated strongly with ATL development and progression. In addition, we identified 22 genes down-regulated due to promoter hypermethylation in HTLV-1-infected T-cells, including THEMIS, LAIR1, and RNF130, which negatively regulate T-cell receptor (TCR) signaling. Phosphorylation of ZAP-70, a transducer of TCR signaling, was dysregulated in HTLV-1-infected cell lines but was normalized by re-expression of THEMIS. Therefore, we hypothesized that DNA hypermethylation contributes to growth advantages in HTLV-1-infected cells during ATL leukemogenesis. To test this idea, we investigated the anti-ATL activities of OR-1200 and OR-2100 (OR21), novel decitabine (DAC) prodrugs with enhanced oral bioavailability. Both DAC and OR21 inhibited cell growth, accompanied by global DNA hypomethylation, in xenograft tumors established by implantation of HTLV-1-infected cells. OR21 was less hematotoxic than DAC, whereas tumor growth inhibition was almost identical between the two compounds, making it suitable for long-term treatment of ATL patient-derived xenograft mice. Our results demonstrate that regional DNA hypermethylation is functionally important for ATL leukemogenesis and an effective therapeutic target.
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影响因子：
64.8
作者：
Wartewig T;Kurgyis Z;Keppler S;Pechloff K;Hameister E;Öllinger R;Maresch R;Buch T;Steiger K;Winter C;Rad R;Ruland J
通讯作者：
Ruland J
影响因子：
30.3
作者：
Mesri EA;Feitelson MA;Munger K
通讯作者：
Munger K
影响因子：
5.7
作者：
Venturelli, Sascha;Berger, Alexander;Bitzer, Michael
通讯作者：
Bitzer, Michael
影响因子：
11.2
作者：
Yoo, Christine B.;Jeong, Shinwu;Jones, Peter A.
通讯作者：
Jones, Peter A.
影响因子：
24.7
作者：
Garcia-Manero, Guillermo;Roboz, Gail;Walsh, Katherine;Kantarjian, Hagop;Ritchie, Ellen;Kropf, Patricia;O'Connell, Casey;Tibes, Raoul;Lunin, Scott;Rosenblat, Todd;Yee, Karen;Stock, Wendy;Griffiths, Elizabeth;Mace, Joseph;Podoltsev, Nikolai;Berdeja, Jesus;Jabbour, Elias;Issa, Jean-Pierre J.;Hao, Yong;Keer, Harold N.;Azab, Mohammad;Savona, Michael R.
通讯作者：
Savona, Michael R.