Zhang Meili, Mathews Griner Lesley A, Ju Wei, Duveau Damien Y, Guha Rajarshi, Petrus Michael N, Wen Bernard, Maeda Michiyuki, Shinn Paul, Ferrer Marc, Conlon Kevin D, Bamford Richard N, O'Shea John J, Thomas Craig J, Waldmann Thomas A
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick, MD 21702;
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850;
Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12480-5. doi: 10.1073/pnas.1516208112. Epub 2015 Sep 22.
Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokine-dependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.
成人T细胞白血病（ATL）在感染人类T细胞白血病病毒1型（HTLV-1）的个体中发生。目前尚无治愈ATL的疗法。HTLV-1编码的蛋白Tax（来自X基因区域的反式激活因子）上调Bcl-xL（B细胞淋巴瘤-特大）的表达，并激活白细胞介素-2（IL-2）、IL-9和IL-15自分泌/旁分泌系统，导致JAK/STAT信号放大。抑制JAK信号可降低处于隐匿/慢性期的ATL患者外周血单个核细胞（PBMC）依赖细胞因子的体外增殖。目前，两种JAK抑制剂已获批用于人类。在本研究中，我们检测了多种JAK抑制剂在ATL细胞系中的活性。在一项与450多种潜在治疗药物联合的高通量矩阵筛选中检测了选择性JAK抑制剂鲁索替尼，并且Bcl-2/Bcl-xL抑制剂维奈托克被确定为多组分治疗的有力候选药物。注意到该联合用药可强烈激活BAX（Bcl-2相关X蛋白），影响线粒体去极化，并增加半胱天冬酶3/7的活性，从而导致聚ADP核糖聚合酶（PARP）和髓样细胞白血病序列1（Mcl-1）的裂解。鲁索替尼和维奈托克单独使用时显示出适度的抗肿瘤疗效，而在ATL小鼠模型中，联合用药显著降低了肿瘤负荷并延长了生存期。这种联合用药强烈阻断了5例ATL患者PBMC的体外增殖。这些研究为使用抑制JAK信号和抗凋亡蛋白Bcl-xL的药物联合方案对隐匿/慢性ATL患者进行治疗试验提供了支持。
