Pathophysiology of Adult T-cell Leukemia/Lymphoma

成人T细胞白血病/淋巴瘤(ATLL)像大多数T细胞肿瘤一样，迫切需要新的治疗方法 预付款。TALL是典型的T细胞淋巴瘤，表现为多器官浸润和极端治疗。 抵抗。不幸的是，大多数ATL患者在确诊后一年内死亡，而目前的药物治疗方案确实如此。 而不是延长这种令人沮丧的预后。ATLL是由一种复杂的逆转录病毒人类T- 嗜淋巴病毒I型(HTLV-1)。在初次感染后，HTLV-1表达的病毒蛋白，特别是Tax， 通过自分泌转录激活IL-2和IL-2R基因表达，促进淋巴细胞增殖 发信号。ATLL在长潜伏期后出现，但Tax基因通常因甲基化而缺失或沉默。 因此，在疾病晚期，IL-2信号的病毒刺激消失了，但白血病细胞仍然处于高水平。 对利用IL2R共同伽马链(IL2RG)的细胞因子的反应，提示宿主因子的作用 在肿瘤的发展过程中。为了支持这一观点，我们最近在JAK3中发现了11%的功能突变。 而且还注意到了频繁的过度表达和激酶激活。JAK3是一种非受体 酪氨酸激酶与IL2RG结合，转导多种细胞因子受体(IL2R、IL4R、IL7R、 IL9R、IL15R和IL21R)。重要的是，依赖突变JAK3的细胞系 托法替尼是一种特殊的JAK3抑制剂，目前正在自身免疫性疾病患者中进行测试 如类风湿性关节炎和牛皮癣。托法替尼已被报道在三期临床试验中有疗效 类风湿性关节炎，是第一个接近批准的此类化合物。在目标1中，我们将研究体内的 骨髓转导和移植实验中突变JAK3表达的作用。我们将测试 突变株JAK3与CDKN2a-/-和病毒Tax癌基因的协同作用。在目标2中，我们将处理JAK3- 用特异JAK3抑制剂tofacitinib诱导淋巴瘤。在目标3中，我们将探索负面监管者如何 JAK3通路的异常可能参与了ATL的发病过程。我们的目标是及时的，可以有一个 对一种普遍致命的疾病的重大影响，并促进我们对 JAK3‘S在T细胞瘤中的作用

Adult T-cell leukemia/lymphoma (ATLL) like most T-cell neoplasms is in dire need of novel therapeutic advances. Typical of T-cell lymphomas, ATLL presents with multi-organ infiltration and extreme treatment resistance. Unfortunately, most ATLL patients die within one year of diagnosis and current drug regimens do not extend this dismal prognosis. ATLL is initiated by infection from a complex retrovirus, Human T- Lymphotropic Virus type I (HTLV-1). After initial infection, viral proteins expressed by HTLV-1, notably tax, transcriptionally activate expression of IL2 and IL2R genes resulting in lymphoproliferation by autocrine signaling. ATLL manifests after long latency but the tax gene is usually deleted or silenced by methylation. Thus, in late stage disease, the viral stimulus of IL-2 signaling is gone but leukemic cells remain hyper- responsive to cytokines that utilize the IL2R common gamma chain (IL2RG), suggesting a role for host factors in tumor progression. In support of this idea, we recently discovered gain of function mutations in JAK3 in 11% of ATLL patients and also noted frequent overexpression and kinase activation. JAK3 is a non-receptor tyrosine kinase that binds with IL2RG to transduce signals from multiple cytokine receptors (IL2R, IL4R, IL7R, IL9R, IL15R, and IL21R) upon ligand binding. Importantly, cell lines dependent upon mutant JAK3 are sensitive to tofacitinib, a specific JAK3 inhibitor currently being tested in patients with autoimmune diseases such as rheumatoid arthritis and psoriasis. Tofacitinib has been reported to have efficacy in phase III trials of rheumatoid arthritis and is the first such compound nearing approval. In Aim 1, we will investigate the in vivo role of mutant JAK3 expression using bone marrow transduction and transplantation experiments. We will test the cooperativity of mutant JAK3 with Cdkn2a-/- and the viral tax oncogene. In Aim 2, we will treat JAK3- induced lymphomas with tofacitinib, a specific JAK3 inhibitor. In Aim 3, we will explore how negative regulators of the JAK3 pathway may be involved in ATLL pathogenesis. Our aims are well-timed and can have a significant impact on a disease that is universally fatal upon diagnosis and advance our understanding of JAK3’s role in T-cell neoplasia.