Zfx, a novel transcriptional regulator of hematopoiesis

Zfx，一种新型造血转录调节因子

基本信息

批准号：
8106758
负责人：
Boris Reizis
金额：
$ 39.74万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8106758
关键词：
Acute Acute Myelocytic Leukemia Adult Award Blood Cells Bone Marrow Bone Marrow Transplantation Burkitt Lymphoma CDKN2A gene Cell Line Cell Maintenance Cells Commit Data Development Disease Future Gene Targeting Genes Genetic Growth Heart Hematological Disease Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human In Vitro Leukemic Cell Life Lymphocyte Lymphoma Lymphopenia MLLT3 gene Maintenance Malignant Neoplasms Mediating Modeling Molecular Mus Myelogenous Pathway interactions Peripheral Peripheral B-Lymphocyte Procedures Property RNA Interference Regulation Role Signal Transduction Stem cells T-Lymphocyte Testing Therapeutic Zinc Fingers base cell type driving force drug development in vivo leukemia leukemia/lymphoma mouse model neoplastic cell novel novel therapeutic intervention p19ARF progenitor self-renewal stem cell population transcription factor

项目摘要

DESCRIPTION (provided by applicant): The hematopoietic stem cells (HSC) in the adult bone marrow (BM) maintain hematopoiesis by virtue of their unique self-renewal capacity. The self-renewal of HSC is at the heart of BM transplantation, a life-saving procedure in many hematological diseases. Self-renewal appears fundamentally different from proliferation, and requires unique extrinsic signals and intrinsic transcriptional regulators. During the first award cycle, we have identified zinc finger transcription factor Zfx as a novel specific regulator of adult HSC maintenance. Recent evidence suggests that many leukemias are propagated by rare leukemic stem cells (LSC), whereas other leukemia types appear more uniformly aggressive. In either case, the fundamental driving force of leukemia, and a prime target for therapy, is uncontrolled or misplaced self-renewal by leukemic cells. The regulators of normal HSC self-renewal are often "hijacked" by leukemic cells including LSC to facilitate their self-renewal. Indeed, our preliminary results show that Zfx is required for leukemic cell development and/or propagation in several leukemia models. We propose that Zfx is an essential regulator of leukemic cell self-renewal, and as such represents an attractive candidate for future drug development. This hypothesis will be explored using three Specific Aims. First, the role of Zfx in the self-renewal of LSC population in vivo will be explored. Second, the requirement for Zfx in the propagation of aggressive leukemias without a distinct LSC compartment will be analyzed. The third Aim will focus on the molecular mechanism of Zfx activity and its target genes in transformed hematopoietic cells. Altogether, these studies would elucidate a novel genetic pathway regulating self-renewal of leukemic cells, and provide candidates for future development of rational therapeutic approaches against leukemia. PUBLIC HEALTH RELEVANCE: Blood cell cancers such as leukemias arise because blood cells acquire aberrant capacity for uncontrolled propagation, or self-renewal. We have identified a novel gene, Zfx, which appears important for leukemia development and propagation. Studies on the role and mechanism of action of Zfx in leukemia may provide novel therapeutic approaches to the disease.

描述（由申请人提供）：成人骨髓（BM）中的造血干细胞（HSC），凭借其独特的自我更新能力来维持造血。 HSC的自我更新是BM移植的核心，这是许多血液学疾病中挽救生命的程序。自我更新与增殖根本不同，需要独特的外部信号和内在的转录调节器。在第一个奖励周期中，我们将锌指转录因子ZFX确定为成人HSC维护的新型特定调节剂。最近的证据表明，许多白血病是由罕见的白血病干细胞（LSC）传播的，而其他白血病类型似乎更均匀地侵略性。无论哪种情况，白血病的基本驱动力和治疗的主要靶标都是白血病细胞不受控制或放错了的自我更新。正常HSC自我更新的调节剂通常被包括LSC在内的白血病细胞“劫持”，以促进其自我更新。确实，我们的初步结果表明，在几种白血病模型中，ZFX是白血病细胞发育和/或传播所必需的。我们建议ZFX是白血病细胞自我更新的重要调节剂，因此代表了未来药物开发的有吸引力的候选人。该假设将使用三个特定目标探讨。首先，将探索ZFX在体内LSC人群自我更新中的作用。其次，将分析ZFX在没有独特LSC室的侵略性白血病传播中的要求。第三个目标将集中在转化的造血细胞中ZFX活性及其靶基因的分子机制上。总的来说，这些研究将阐明一种新的遗传途径，以调节白血病细胞的自我更新，并为未来开发针对白血病的理性治疗方法提供候选。公共卫生相关性：血细胞癌（如白血病）之所以出现，是因为血细胞具有不受控制的传播或自我更新的异常能力。我们已经确定了一种新型基因ZFX，这对于白血病的发育和传播似乎很重要。关于ZFX在白血病中作用的作用和机制的研究可能为疾病提供新的治疗方法。