Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
J Exp Med. 2010 Dec 20;207(13):2785-92. doi: 10.1084/jem.20101095. Epub 2010 Dec 6.
Chronic HTLV-I (human T cell lymphotropic virus type I) infection may cause adult T cell leukemia/lymphoma (ATL), a disease with dismal long-term prognosis. The HTLV-I transactivator, Tax, initiates ATL in transgenic mice. In this study, we demonstrate that an As(2)O(3) and IFN-α combination, known to trigger Tax proteolysis, cures Tax-driven ATL in mice. Unexpectedly, this combination therapy abrogated initial leukemia engraftment into secondary recipients, whereas the primary tumor bulk still grew in the primary hosts, only to ultimately abate later on. This loss of initial transplantability required proteasome function. A similar regimen recently yielded unprecedented disease control in human ATL. Our demonstration that this drug combination targeting Tax stability abrogates tumor cell immortality but not short-term growth may foretell a favorable long-term efficiency of this regimen in patients.
慢性 HTLV-I（人类 T 细胞淋巴组织病毒 I 型）感染可能导致成人 T 细胞白血病/淋巴瘤（ATL），这是一种预后极差的疾病。HTLV-I 转录激活物 Tax 可引发转基因小鼠的 ATL。在这项研究中，我们证明了一种砷（2）和 IFN-α 的联合治疗，已知可触发 Tax 蛋白水解，从而治愈 Tax 驱动的 ATL 小鼠。出乎意料的是，这种联合治疗方案消除了初始白血病向次级受者的移植能力，而原发性肿瘤仍在原发性宿主中生长，只是最终会逐渐消退。这种初始移植能力的丧失需要蛋白酶体功能。最近，类似的治疗方案在人类 ATL 中取得了前所未有的疾病控制效果。我们的研究表明，这种针对 Tax 稳定性的药物联合治疗方案消除了肿瘤细胞的永生性，但不影响短期生长，这可能预示着该方案在患者中的长期疗效良好。
