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.

像大多数T细胞肿瘤一样，成人T细胞白血病/淋巴瘤（ATLL）迫切需要新的治疗 进步。典型的T细胞淋巴瘤，ATLL呈现多器官浸润和极端处理 反抗。不幸的是，大多数ATLL患者在诊断和当前药物方案的一年内死亡 不要扩大这种惨淡的预后。 ATLL是由复杂逆转录病毒的感染引发的，人类T- 淋巴病毒I型（HTLV-1）。初次感染后，由HTLV-1表达的病毒蛋白，特别是税收， 转录激活IL2和IL2R基因的表达，导致自分泌产生淋巴增生 信号。 ATLL在长潜伏期后表现出来，但税收基因通常被甲基化删除或沉默。 在后期疾病中，IL-2信号传导的病毒刺激消失了，但白血病细胞仍然是高度的 对利用IL2R普通伽马链（IL2RG）的细胞因子的反应敏感，这表明宿主因素的作用 在肿瘤进展中。为了支持这个想法，我们最近发现JAK3中的功能突变增益为11％ ATLL患者的经常指出过表达和激酶激活。 JAK3是一个无受体 酪氨酸激酶与IL2RG结合以翻译来自多种细胞因子受体的信号（IL2R，IL4R，IL7R， IL9R，IL15R和IL21R）在配体结合后。重要的是，取决于突变jak3的细胞系是 对Tofacitinib敏感，Tofacitinib是一种特定的JAK3抑制剂，目前正在自身免疫性疾病患者中进行测试 例如类风湿关节炎和牛皮癣。据报道，tofacitinib在III期试验中具有效率 类风湿关节炎，是第一个接近批准的化合物。在AIM 1中，我们将研究体内 使用骨髓转导和移植实验突变JAK3表达的作用。我们将测试 突变JAK3与CDKN2A - / - 的协调和病毒税癌基因。在AIM 2中，我们将对待JAK3- 特异性JAK3抑制剂Tofacitinib诱导淋巴瘤。在AIM 3中，我们将探讨负面监管机构如何 JAK3途径的ATLL发病机理可能涉及。我们的目标是适时的，可以 对普遍致命诊断并提高我们对疾病的重大影响 JAK3在T细胞肿瘤中的作用。