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

项目总结 成人T细胞白血病/淋巴瘤(ATL)发生在感染HTLV-1的人中，是一种侵袭性疾病 辅助性T淋巴细胞的恶性，与高钙血症和溶骨性病变有关。我们发现 HTLV-1Tax病毒癌基因对ATL的发生和溶骨性骨破坏都是至关重要的 通过非细胞自主作用于骨吸收破骨细胞(OC)。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(Dkk1和skerostin) 成骨细胞分化(OB)。未成熟的OB产生更高水平的OC促进、RANKL和STEM 细胞生态位归巢因子SDF1。我们假设在HTLV-1感染的T细胞中Tax和Hbz的表达 转化的ATL细胞重新编程骨微环境，对于HTLV-1诱导的 细胞转化和进展。我们提出了以下目标：目标1：确定Hbz和Tax 在HTLV-1感染、转化和白血病进展过程中调节骨骼微环境。目标 2：Hedgehog(HH)介导的肿瘤-骨细胞相互作用的Tax/Hbz依赖特征 路径。目的3：确定Tax和/或HBZ对调节骨骼的WNT途径基因的作用 ATL发生发展过程中的微环境。该项目将涉及必要的合作 与项目1和4共享数据和试剂(对于体内HBZ+和TAX+肿瘤模型，TAX/Hbz 项目2、4和核心B(蛋白质组学分析)、项目1和核心A(统计 和数据分析)和核心C(人源化HTLV-1-His的产生和组织学特征 老鼠)。与PPG的其他成员一起，我们的长期目标是确定HTLV-1病毒的新角色 感染后和白血病期间骨肿瘤微环境重编程中的癌基因 通过非细胞自主机制实现转型，促进新能源的合理发展 ATL的治疗方法。

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.