Project 3: Effect of HTLV-1 Viral Oncogenes on the Bone Microenvironment in ATL

项目3：HTLV-1病毒癌基因对ATL骨微环境的影响

• 批准号: 8742041
• 负责人: Katherine Nelson Weilbaecher
• 金额: $ 29.89万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742041
• 关键词: Adult T-Cell Leukemia/Lymphoma; Affect; Biology; Bone Marrow; Bone Tissue; Breast; CXCL12 gene; Cancer Model; Cell Communication; Cells; Collaborations; Coupling; Data; Dependence; Development; Erinaceidae; Factor Analysis; Generations; Genes; Genetic; Goals; Growth; Helper-Inducer T-Lymphocyte; Histologic; Homing; Human T-lymphotropic virus 1; Hypercalcemia; In Vitro; Individual; Infection; Lesion; Ligands; Light; Lytic Metastatic Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Mediating; Modeling; Multiple Myeloma; Mus; Oncogenes; Oncogenic; Osteoblasts; Osteoclasts; Osteolysis; Osteolytic; Pathway interactions; Property; Proteins; Proteomics; Reagent; Refractory; Retroviridae; Role; Staging; Statistical Data Interpretation; Stromal Cells; T-Lymphocyte; TNFSF11 gene; Taxes; Therapeutic; Tumor-Derived; Viral; Viral Oncogene; Virus; Virus Diseases; WNT Signaling Pathway; bZIP Domain; bone; bone cell; bone invasion; bone loss; bone turnover; chemotherapy; data sharing; in vivo; leukemia; long bone; member; metaplastic cell transformation; mutant; neoplastic cell; novel therapeutic intervention; osteoblast differentiation; overexpression; paracrine; prevent; smoothened signaling pathway; soft tissue; stem cell niche; transcription factor; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY Adult T-cell leukemia/lymphoma (ATL) develops in people infected with HTLV-1 and is an aggressive malignancy of helper T-lymphocytes, associated with hypercalcemia and osteolytic bone lesions. We found that the HTLV-1 tax viral oncogene is critical to both ATL development and to osteolytic bone destruction through non-cell autonomous effects on bone resorbing osteoclasts (OC). We discovered that Tax and the newly identified viral oncogene, HTLV-1 basic leucine zipper, Hbz, can regulate the expression of paracrine factors that modulate the tumor microenvironment in bone, specifically through the expression of Hedgehog (Hh) ligands which promote bone turnover and WNT modulators (DKK1 and sclerostin) which inhibit differentiation of osteoblasts (OB). Immature OB produce higher levels of the OC promoting, RANKL, and stem cell niche homing factor, SDF1. We hypothesize that Tax and Hbz expression in HTLV-1-infected T cells and transformed ATL cells reprogram the bone microenvironment and are essential for both HTLV-1-induced cellular transformation and progression. We propose the following aims: Aim 1: Determine how Hbz and Tax modulate the bone microenvironment during HTLV-1 infection, transformation, and leukemic progression. Aim 2: Characterize Tax/Hbz-dependence on tumor-bone cell interactions mediated by the Hedgehog (Hh) pathway. Aim 3: Determine the roles of Tax and/or HBZ on WNT pathway genes that modulate the bone microenvironment during ATL development and progression. This project will involve essential collaborations and sharing of data and reagents with Projects 1 and 4 (for in vivo HBZ+ and Tax+ tumor models, Tax/Hbz mutant viruses and cells), Project 2, 4, and Core B (proteomic analyses), Project 1 and Core A (statistical and data analyses) and Core C (generation of and histologic characterization of humanized HTLV-1-HIS mice). Together with the other PPG members, our long-term goal is to identify new roles for HTLV-1 viral oncogenes in reprogramming the tumor microenvironment in bone after infection and during leukemic transformation through non-cell autonomous mechanisms leading to the rational development of new therapeutic approaches for ATL.

项目摘要 成人T细胞白血病/淋巴瘤（ATL）发生在感染HTLV-1的人群中，是一种侵袭性淋巴瘤。 辅助性T淋巴细胞的恶性肿瘤，与高钙血症和溶骨性病变相关。我们发现 HTLV-1 tax病毒癌基因对ATL的发展和溶骨性骨破坏都是至关重要的 通过对骨吸收破骨细胞（OC）的非细胞自主作用。我们发现税收和 新发现的病毒癌基因HTLV-1碱性亮氨酸拉链（Hbz）可以调节旁分泌的表达 调节骨中肿瘤微环境的因子，特别是通过Hedgehog的表达 (Hh)促进骨转换的配体和抑制骨转换的WNT调节剂（DKK 1和硬化蛋白） 成骨细胞（OB）的分化。未成熟的OB产生更高水平的OC促进、RANKL和干细胞， 细胞巢归巢因子SDF 1。我们假设Tax和Hbz在HTLV-1感染的T细胞中的表达， 转化的ATL细胞重新编程骨微环境，并且对于HTLV-1诱导的 细胞的转化和发展。我们提出以下目标：目标1：确定Hbz和税收如何 在HTLV-1感染、转化和白血病进展期间调节骨微环境。目的 2：表征Tax/Hbz对由刺猬（Hh）介导的肿瘤-骨细胞相互作用的依赖性 通路目的3：确定Tax和/或HBZ对调节骨的WNT途径基因的作用 微环境在ATL的发展和进步。该项目将涉及重要的合作 与项目1和4共享数据和试剂（用于体内HBZ+和Tax+肿瘤模型，Tax/Hbz 突变病毒和细胞）、项目2、4和核心B（蛋白质组学分析）、项目1和核心A（统计学分析） 和数据分析）和核心C（人源化HTLV-1-HIS的产生和组织学表征 小鼠）。与其他PPG成员一起，我们的长期目标是确定HTLV-1病毒的新作用， 癌基因在感染后和白血病期间骨中肿瘤微环境重编程中的作用 通过非细胞自主机制的转化，导致新的 ATL的治疗方法。