Zfx, a novel transcriptional regulator of hematopoiesis

Zfx，一种新型造血转录调节因子

• 批准号: 8443412
• 负责人: Boris Reizis
• 金额: $ 37.92万
• 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/8443412
• 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; MLL-AF9; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Myelogenous; Pathway interactions; Peripheral; Peripheral B-Lymphocyte; Procedures; Property; RNA Interference; Regulation; Role; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Zinc Fingers; base; cell type; driving force; drug development; in vivo; leukemia; leukemia/lymphoma; leukemic stem cell; mouse model; neoplastic cell; novel; novel therapeutic intervention; p19ARF; progenitor; public health relevance; 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.

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功能。 HSC 的自我更新是骨髓移植的核心，骨髓移植是许多血液疾病的挽救生命的手术。自我更新似乎与增殖根本不同，并且需要独特的外在信号和内在转录调节因子。在第一个奖励周期中，我们已确定锌指转录因子 Zfx 是成人 HSC 维持的新型特异性调节因子。 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具侵袭性。无论哪种情况，白血病的根本驱动力和治疗的主要目标都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，在几种白血病模型中，Zfx 是白血病细胞发育和/或增殖所必需的。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。将使用三个具体目标来探讨这一假设。首先，将探讨 Zfx 在体内 LSC 群体自我更新中的作用。其次，将分析没有明显 LSC 区室的侵袭性白血病传播中对 Zfx 的需求。第三个目标将重点研究转化造血细胞中Zfx活性及其靶基因的分子机制。总而言之，这些研究将阐明调节白血病细胞自我更新的新遗传途径，并为未来开发合理的白血病治疗方法提供候选者。