Pathophysiology of Adult T-cell Leukemia/Lymphoma

成人 T 细胞白血病/淋巴瘤的病理生理学

基本信息

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
项目类别：
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

项目摘要

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）：与大多数 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展。 ATLL 是 T 细胞淋巴瘤的典型特征，具有多器官浸润和极端的治疗耐药性。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并不能延长这种令人沮丧的预后。 ATLL 是由复杂的逆转录病毒、人类 T 淋巴细胞病毒 I 型 (HTLV-1) 感染引发的。初次感染后，HTLV-1 表达的病毒蛋白（尤其是 Tax）转录激活 IL2 和 IL2R 基因的表达，通过自分泌信号传导导致淋巴增殖。 ATLL 在长时间潜伏期后显现，但tax 基因通常会因甲基化而被删除或沉默。因此，在疾病晚期，IL-2信号传导的病毒刺激消失，但白血病细胞仍然对利用IL2R共同γ链（IL2RG）的细胞因子高度敏感，这表明宿主因子在肿瘤进展中发挥作用。为了支持这一观点，我们最近发现 11% 的 ATLL 患者的 JAK3 功能突变增加，并且还注意到频繁的过度表达和激酶激活。 JAK3 是一种非受体酪氨酸激酶，可与 IL2RG 结合，在配体结合后转导来自多种细胞因子受体（IL2R、IL4R、IL7R、IL9R、IL15R 和 IL21R）的信号。重要的是，依赖突变型 JAK3 的细胞系对托法替布敏感，托法替布是一种特异性 JAK3 抑制剂，目前正在类风湿性关节炎和牛皮癣等自身免疫性疾病患者中进行测试。据报道，托法替布在类风湿性关节炎的 III 期试验中具有疗效，并且是第一个即将获得批准的此类化合物。在目标 1 中，我们将使用骨髓转导和移植实验研究突变型 JAK3 表达的体内作用。我们将测试突变体 JAK3 与 Cdkn2a-/- 和病毒税癌基因的协同作用。在目标 2 中，我们将用托法替尼（一种特定的 JAK3 抑制剂）治疗 JAK3 诱导的淋巴瘤。在目标 3 中，我们将探讨 JAK3 通路的负调节因子如何参与 ATLL 发病机制。我们的目标恰逢其时，能够对诊断后普遍致命的疾病产生重大影响，并增进我们对 JAK3 在 T 细胞肿瘤中作用的理解。