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：
8442075
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/8442075
关键词：
Adult 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 Leukemia 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）：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展。 T细胞淋巴瘤的典型特征，ATLL呈现具有多器官浸润和极端治疗能力的ATLL。不幸的是，大多数ATLL患者在诊断后的一年内死亡，目前的药物方案不会扩大这种惨淡的预后。 ATLL是由复杂逆转录病毒，人类T-淋巴机病毒I型（HTLV-1）的感染引发的。最初感染后，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，从而导致自分泌信号传导淋巴细胞增生。 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。因此，在晚期疾病中，IL-2信号传导的病毒刺激消失了，但白血病细胞对利用IL2R普通伽马链（IL2RG）的细胞因子有效反应，这表明宿主因子在肿瘤进展中的作用。为了支持这一想法，我们最近发现了11％的ATLL患者中JAK3的功能突变增益，并且还指出了频繁的过表达和激酶激活。 JAK3是一种非受体酪氨酸激酶，它与IL2RG结合，以从多个细胞因子受体（IL2R，IL4R，IL4R，IL7R，IL9R，IL9R，IL15R和IL21R）中传递信号。重要的是，依赖于突变体Jak3的细胞系对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（如类风湿关节炎和牛皮癣）中进行测试。据报道，Tofacitinib在类风湿关节炎的III期试验中具有功效，并且是第一个接近批准的这种化合物。在AIM 1中，我们将使用骨髓转导和移植实验研究突变JAK3表达的体内作用。我们将测试突变JAK3与CDKN2A - / - 和病毒税癌基因的合作性。在AIM 2中，我们将使用特定的JAK3抑制剂Tofacitinib治疗JAK3诱导的淋巴瘤。在AIM 3中，我们将探讨JAK3途径的负调节因子如何参与ATLL发病机理。我们的目标是恰当的，可以对疾病产生重大影响，该疾病在诊断中普遍致命，并促进我们对JAK3在T细胞肿瘤中的作用的理解。