Zfx, a novel transcriptional regulator of hematopoiesis

描述(申请人提供)：成人骨髓中的造血干细胞(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，在许多血液疾病中，骨髓移植是一种挽救生命的程序。自我更新似乎从根本上不同于增殖，它需要独特的外部信号和内在的转录调节因子。在第一个获奖周期中，我们已经确定锌指转录因子Zfx是一种新的成人HSC维持的特异性调节因子。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，而其他类型的白血病似乎更具侵袭性。在任何一种情况下，白血病的根本驱动力，也是治疗的首要目标，都是白血病细胞不受控制或错位的自我更新。正常的HSC自我更新的调节者经常被包括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因子，因此是未来药物开发的一个有吸引力的候选者。我们将通过三个具体目标来探讨这一假设。首先，我们将探讨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间隔的侵袭性白血病的传播中的需求。第三个目标将集中在Zfx活性的分子机制及其在转化的造血细胞中的靶基因。综上所述，这些研究将阐明调节白血病细胞自我更新的新的遗传途径，并为未来开发合理的白血病治疗方法提供候选。 公共卫生相关性：白血病等血细胞癌的发生是因为血细胞获得了不受控制的繁殖或自我更新的异常能力。我们已经鉴定出一个新的基因Zfx，它似乎对白血病的发生和繁殖很重要。研究Zfx在白血病中的作用和作用机制可能为白血病的治疗提供新的途径。

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.