IRF4/8在造血系统发育调控及白血病发生中的作用及机制

The structure closely related, hematopoietic specific interferon regulatory factors, IRF4 and IRF8, play critical roles in the development of multiple lineages of hematopoietic cells. They have both unique and overlapping functions. They both also play critical roles in the development of hematologic malignancies. IRF4 was originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. Expression of IRF4 is essential for the maintenance of multiple myeloma cells, suggesting that IRF4 is a potential target for the development of cancer therapies. Our research, however, establish that IRF4 functions as a tumor suppressor in myeloid lineage and in early B cell development. We have also found that IRF8 plays an important role in regulating the cell cycle of long-term hematopoietic stem cells (HSC) and that IRF8 is not only a tumor suppressor in myeloid cells, but also functions as a tumor suppressor together with IRF4 in preventing the development of mediastinal B-lymphoblastic lymphoma. The multifaceted roles of IRF4 and IRF8 in hematopoiesis and tumorigenesis raise caution in the development of cancer therapies targeting these molecules. In this proposal we will focus on dissecting the molecular mechanisms by which IRF8 regulates the cell cycle of HSC, as well as the mechanisms by which IRF4 and IRF8 function, alone and together, as tumor suppressors. These studies will help for the development of targeted therapies again IRF4 and IRF8-related hematological diseases and will shed new lights into the regulation of HSC cell cycle. Since the precise regulation of HSC cell cycle is critical for their ability to self-renew and to generate all cell types of the blood lineages throughout the lifetime of an individual, the proposed studies would also help for the development of stem cell based therapies.

IRF4和IRF8是造血系统特异表达、结构相近的干扰素调节因子，在造血系统发育、白血病发生等方面具有重要功能。我们的前期研究揭示了IRF8是造血干细胞细胞周期的重要调控因子；虽然IRF4在多发性骨髓瘤中是起驱动作用的癌基因，它在髓细胞及早期B淋巴细胞发育中具有抑制白血病发生的功能；IRF8不仅在髓细胞有抑癌功能，它与IRF4共同作用抑制纵膈B淋巴母细胞瘤的发生。确定IRF4和IRF8在造血系统发育及恶性肿瘤发生中的作用及机制对于研发相关疾病的靶向治疗至关重要。同时，造血干细胞细胞周期的精确调控是其自我更新、保持终身提供分化细胞能力的关键之一。本项目将深入研究IRF8在造血干细胞中的作用机制及其抑癌机制、IRF4的抑癌机制及IRF4/IRF8在髓系和淋系肿瘤发生中的相互作用及机制，为IRF4和IRF8相关造血系统疾病靶向治疗及干细胞生物治疗奠定理论基础。

IRF4和IRF8是造血系统特异表达、结构相近的干扰素调节因子，在造血系统发育、白血病发生等方面具有重要功能。本项目诣在深入研究IRF8在造血干细胞中的作用机制及其抑癌机制、IRF4的抑癌机制及IRF4/IRF8在髓系和淋系肿瘤发生中的相互作用及机制，为IRF4和IRF8 相关造血系统疾病靶向治疗及干细胞生物治疗奠定理论基础。.在IRF8对造血干细胞的作用与机制研究中，我们发现IRF8调控造血干细胞的数量及功能，通过单细胞转录组学及进一步功能研究，我们发现IRF8能直接调控天然免疫受体TLR9（Toll-like receptor 9）表达，TLR9信号激活后，免疫细胞分泌及释放细胞因子，继而影响造血干细胞的数量及功能。本研究揭示了IRF8通过调控天然免疫来调节造血，在造血干细胞的稳态维持及自我更新中起重要作用。在IRF4/IRF8在血液系统肿瘤研究方面，我们发现IRF4和IRF8表达与骨髓增生性肿瘤疾病进展密切相关，也是原发性血小板增多症对羟基脲反应的主要决定因素，此研究为骨髓增生性肿瘤患者风险分层及精准治疗提供了依据。我们在签定IRF4结合蛋白时发现，泛素底物连接分子DCAF8与IRF4间有较强的相互作用，进一步研究发现DCAF8缺陷小鼠呈现明显的造血干细胞衰老表型，本研究将为揭示造血干细胞衰老的分子机制，开发针对相应的治疗手段提供基础。