PTIP在急性髓系白血病干细胞的干性维持与自我更新中的作用与分子机制研究

Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, which derives from a rare cell population--leukemia stem cells (LSCs). LSCs possess the capacity to self-renew and differentiate into leukemia cells, and are insensitive to drug treatment. Increasing evidence indicates that the existence of LSCs is the major reason for AML relapse in clinic. Thus, one of the major issues in current AML biology is to understand the molecular mechanisms of maintenance and drug sensitivity of LSCs. PTIP is a critical component of histone methyltransferase complex MLL3/4, and also plays an important role in DNA repair. However, the biological function of PTIP in leukemogenesis and LSCs remains unknown. We observed higher level of PTIP transcript in AML patient-derived leukemia cells. Interestingly, we found that loss of PTIP inhibits leukemia cell proliferation and clonogenic ability by inducing cell differentiation and apoptosis. Additionally, we also observed that PTIP regulates the expression of HOXA9 and MEIS1, the key genes of maintaining LSCs. Together, these preliminary findings imply PTIP plays a crucial role in leukemogenesis and LSCs. Therefore, in this project, we will further investigate the molecular mechanisms by which PTIP regulates LSCs maintenance, and explore the role of PTIP in mediating drug sensitivity of LSCs. This study will bring keen insight into the mechanistic understanding of PTIP function on leukemogenesis and LSCs, and might provide a potential therapeutic strategy against AML.

急性髓系白血病是一类克隆性的恶性血液肿瘤，起源于具有自我更新能力和分化潜能的少量细胞群体--白血病干细胞。这类细胞具有药物抗性，是白血病耐药和复发的主要原因。所以，对白血病干细胞干性维持与自我更新、耐药的分子机理的研究，是目前本领域亟待解决的重大问题之一。PTIP是组蛋白甲基转移酶MLL3/4复合物上的重要组成蛋白，并参与DNA损伤修复。但其在白血病及白血病干细胞中的生物学功能尚无报道。我们前期发现PTIP在急性髓系白血病人来源细胞中高表达；PTIP缺失促进白血病细胞分化和凋亡，显著抑制细胞增殖和克隆形成能力。还发现PTIP参与调控白血病干细胞关键基因HOXA9和MEIS1的表达。基于此，本项目拟深入研究PTIP在急性髓系白血病发生发展和白血病干细胞干性维持与自我更新中的作用与分子机制，探索其在白血病干细胞药物抗性的机理，从而为急性髓系白血病治疗提供新的策略，具有重要的临床应用意义。

急性髓系白血病 (Acute myeloid leukemia，AML) 是最常见的恶性血液肿瘤，由髓系祖细胞分化阻滞、恶性增殖引起的克隆性疾病。AML起源于具有自我更新能力和分化潜能的少量细胞群体--白血病干细胞。深入研究白血病干细胞干性维持与自我更新的分子机制，对理解AML致病机理和靶向白血病干细胞起关键作用。本研究揭示了PTIP对AML发生发展和造血干细胞功能维持具有重要作用。发现了PTIP缺失抑制AML细胞增殖，促进细胞凋亡和分化，抑制AML发生发展和白血病干细胞的功能；发现了PTIP维持了LT-HSCs的静息状态进而维持了其功能；揭示了PTIP调控LT-HSCs线粒体能量代谢和ROS通路相关基因表达；阐明了TGFβ信号通路调控了PTIP与53BP1的相互作用，从而调控PTIP参与DNA损伤修复。本项目执行期间在Cell Stem Cell、Stem Cells Translational Medicine等杂志发表3篇论文, 另有2篇SCI论文待发表。研究团队在本项目执行期间也获得国家自然科学基金优秀青年基金、国家重点研发计划、湖北省杰出青年基金等项目的资助。