Pathophysiology of Adult T-cell Leukemia/Lymphoma

成人 T 细胞白血病/淋巴瘤的病理生理学

• 批准号: 9591306
• 负责人: Utpal P Dave
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2017-10-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9591306
• 关键词: Adult T-Cell Leukemia/Lymphoma; Affect; Age-Years; Autocrine Communication; Autoimmune Diseases; Binding; Bone Marrow; Cell Line; Complex; Cytokine Receptors; Data; Diagnosis; Disease; Enzymes; Female; Functional disorder; Genes; Genetic Transcription; Grant; Growth; Human T-lymphotropic virus 1; IL2 gene; IL2RA gene; IL4R gene; IL7R gene; Infection; Infiltration; Integration Host Factors; Interleukin 2 Receptor Gamma; Interleukin-2; JAK3 gene; Laboratories; Leukemic Cell; Ligand Binding; Lymphoma; Malignant Neoplasms; Methylation; Modeling; Mutation; Neoplasms; Oncogenes; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Population; Psoriasis; Regimen; Reporting; Resistance; Retroviridae; Rheumatoid Arthritis; Role; Signal Transduction; Stimulus; T-Cell Lymphoma; T-Cell and NK-Cell Neoplasm; T-Lymphocyte; Taxes; Testing; Transplantation; Veterans; Viral; Viral Proteins; cytokine; experimental study; gain of function mutation; in vivo; inhibitor/antagonist; interleukin-21 receptor; leukemia/lymphoma; male; mutant; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; phase III trial; standard care; tax Genes; therapy resistant; tumor progression

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.

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。ATLL是典型的T细胞淋巴瘤，表现为多器官浸润和极端治疗 阻力不幸的是，大多数ATLL患者在诊断后一年内死亡，而目前的药物治疗方案确实如此。 而不是延续这种悲观的预测。ATLL是由一种复杂的逆转录病毒感染引发的， 嗜热病毒I型（HTLV-1）。在初始感染后，由HTLV-1表达的病毒蛋白，特别是tax， 转录激活IL 2和IL 2 R基因的表达，通过自分泌导致淋巴细胞增殖 发信号。ATLL在长潜伏期后出现，但tax基因通常被甲基化删除或沉默。 因此，在晚期疾病中，IL-2信号的病毒刺激消失，但白血病细胞仍保持高表达。 对利用IL 2 R共同γ链（IL 2 RG）的细胞因子有反应，表明宿主因子在 在肿瘤进展中。为了支持这一观点，我们最近发现11%的人中JAK 3的功能突变增加， 的ATLL患者，也注意到频繁的过度表达和激酶激活。JAK 3是一种非受体 酪氨酸激酶与IL 2 RG结合，以抑制来自多种细胞因子受体（IL 2 R，IL 4 R，IL 7 R， IL 9 R、IL 15 R和IL 21 R）。重要的是，依赖于突变JAK 3的细胞系是 对托法替尼敏感，这是一种特异性JAK 3抑制剂，目前正在自身免疫性疾病患者中进行测试 例如类风湿性关节炎和牛皮癣。据报道，托法替尼在以下III期试验中具有疗效： 这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 使用骨髓转导和移植实验研究突变型JAK 3表达的作用。我们将测试 突变JAK 3与Cdkn 2a-/-和病毒tax癌基因的协同性。在目标2中，我们将处理JAK 3- 用特异性JAK 3抑制剂托法替尼诱导淋巴瘤。在目标3中，我们将探讨负监管机构如何 JAK 3通路的激活可能参与了ATLL的发病机制。我们的目标是适时的， 对一种在诊断时普遍致命疾病产生重大影响，并促进我们对 JAK 3在T细胞瘤形成中的作用。