Zfx, a novel transcriptional regulator of hematopoiesis

Zfx，一种新型造血转录调节因子

• 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
• 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

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（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维持造血。造血干细胞的自我更新是骨髓移植的核心，骨髓移植是许多血液病的救命手术。自我更新似乎从根本上不同于增殖，需要独特的外在信号和内在的转录调节因子。在第一个奖励周期，我们已经确定了锌指转录因子Zfx作为一种新的特异性调节成人HSC的维护。 最近的证据表明，许多白血病是由罕见的白血病干细胞（LSC）繁殖的，而其他白血病类型似乎更具侵略性。在任何一种情况下，白血病的基本驱动力和治疗的主要目标是白血病细胞不受控制或错位的自我更新。正常HSC自我更新的调节因子经常被包括LSC在内的白血病细胞“劫持”以促进其自我更新。事实上，我们的初步结果表明，Zfx是所需的白血病细胞的发展和/或繁殖在几个白血病模型。我们认为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者。我们将使用三个具体目标来探讨这一假设。首先，将探索Zfx在体内LSC群体自我更新中的作用。其次，将分析Zfx在没有明显LSC区室的侵袭性白血病传播中的需求。第三个目标将集中于Zfx活性的分子机制及其在转化造血细胞中的靶基因。总之，这些研究将阐明一个新的遗传途径调节白血病细胞的自我更新，并提供候选人为未来发展的合理的治疗方法对白血病。 公共卫生相关性：血细胞癌症如白血病的出现是因为血细胞获得了不受控制的增殖或自我更新的异常能力。我们已经确定了一个新的基因，Zfx，这似乎是重要的白血病的发展和传播。研究Zfx在白血病中的作用及其作用机制，可能为白血病的治疗提供新的思路。