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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）：