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: 8624521
• 负责人: Utpal P Dave
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 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 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624521
• 关键词: Adult T-Cell Leukemia/Lymphoma; Affect; Africa; Age; Age of Onset; Age-Years; Animals; Area; Autocrine Communication; Autoimmune Diseases; Binding; Biological Assay; Bone Marrow; Bone Marrow Cells; Caribbean region; Cell Line; Cells; Clinical; Complex; Cytokine Receptors; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Diagnosis; Disease; Drug resistance; Ensure; Enzymes; Feedback; Female; Functional disorder; Gender; Genes; Grant; Growth; Human; Human T-lymphotropic virus 1; IL2 gene; IL2RA gene; IL4R gene; IL7R gene; Infection; Infiltration; Integration Host Factors; Interleukin 2 Receptor Gamma; Interleukin-2; Investigation; JAK3 gene; Janus kinase 3; Japan; Laboratories; Leukemic Cell; Ligand Binding; Lymphoma; Malignant Neoplasms; Methylation; Modeling; Mus; Mutation; Neoplasms; Oncogenes; Organ; Organism; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphotransferases; Population; Protein Tyrosine Kinase; Proteins; Psoriasis; Recombinants; Regimen; Regulation; Reporting; Resistance; Retroviridae; Rheumatoid Arthritis; Role; Sampling; Signal Transduction; Signal Transduction Pathway; Staging; Stimulus; T-Cell Lymphoma; T-Cell and NK-Cell Neoplasm; T-Lymphocyte; Taxes; Testing; Time; Transplantation; Tumor Suppressor Proteins; Veterans; Viral; Viral Proteins; Virus; Virus Diseases; Wild Type Mouse; Woman; cytokine; drug sensitivity; effective therapy; gain of function; gain of function mutation; in vivo; inhibitor/antagonist; insight; interleukin-15 receptor; interleukin-21 receptor; leukemia; leukemia/lymphoma; male; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; public health relevance; research study; response; standard care; tax Genes; trafficking; tumor; tumor progression

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 成人T细胞白血病/淋巴瘤（ATLL）像大多数T细胞肿瘤一样，迫切需要新的治疗进展。ATLL是典型的T细胞淋巴瘤，表现为多器官浸润和极端的治疗抵抗。不幸的是，大多数ATLL患者在诊断后一年内死亡，目前的药物治疗方案不能延长这种令人沮丧的预后。ATLL是由一种复杂的逆转录病毒--人嗜T细胞病毒I型（HTLV-1）感染引起的.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，从而通过自分泌信号传导导致淋巴细胞增殖。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信号传导的病毒刺激消失，但白血病细胞对利用IL 2 R共同γ链（IL 2 RG）的细胞因子保持高应答，表明宿主因子在肿瘤进展中的作用。为了支持这一观点，我们最近在11%的ATLL患者中发现了JAK 3功能突变的获得，并且还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，其在配体结合后与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）的信号。重要的是，依赖突变JAK 3的细胞系对托法替尼敏感，托法替尼是一种特异性JAK 3抑制剂，目前正在类风湿性关节炎和银屑病等自身免疫性疾病患者中进行测试。据报道，托法替尼在类风湿性关节炎的III期试验中有效，是第一个接近批准的此类化合物。在目标1中， 我们将使用骨髓转导和移植实验研究突变JAK 3表达的体内作用。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，我们将用特异性JAK 3抑制剂托法替尼治疗JAK 3诱导的淋巴瘤。在目标3中，我们将探讨JAK 3通路的负调节因子如何参与ATLL发病机制。我们的目标是适时的，可以对诊断时普遍致命的疾病产生重大影响，并促进我们对JAK 3在T细胞瘤形成中作用的理解。