Zerella Jiarna R, Homan Claire C, Arts Peer, Brown Anna L, Scott Hamish S, Hahn Christopher N
Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.
Front Oncol. 2023 Jun 12;13:1183318. doi: 10.3389/fonc.2023.1183318. eCollection 2023.
Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.
转录因子（TFs）作为众多发育途径的关键调节因子发挥着至关重要的作用，其高度调控且组织严密的网络对于确定组织发育的时间和模式至关重要。TFs可作为原始造血和确定性造血的主要调节因子，严格控制造血干细胞和祖细胞（HSPCs）的行为。这些网络控制着HSPCs的功能调节，包括自我更新、增殖和分化动态，而这些对于正常造血至关重要。明确这些造血转录网络的关键参与者和动态对于理解正常造血以及TFs及其网络中的基因畸变如何导致包括骨髓衰竭（BMF）和血液系统恶性肿瘤（HM）在内的造血疾病至关重要。尽管它们在血液学发育中有着多方面且复杂的参与，但基因筛查的进展以及精妙的多组学和模型系统研究正在揭示造血TFs如何相互作用并形成网络以实现正常细胞命运及其在疾病病因学中的作用。本综述聚焦于易导致BMF和HM的TFs，确定潜在的新型候选易感性TF基因，并研究导致这些表型的假定生物学机制。更好地理解造血TFs的遗传学和分子生物学，以及确定易导致BMF和HM的新基因和遗传变异，将加速预防策略的开发，改善临床管理和咨询，并有助于确定这些疾病的靶向治疗方法。
