造血干细胞在临床上需求量巨大，但来源却十分受限。获得可用于移植的、人的诱导多能干细胞（iPSC）来源的造血干祖细胞（iHSPC）是血液领域的热点和难点，迄今国际上只有极少数的成功报道, 但方法复杂、效率低下。我们前期通过单因子MLL-AF4的介导获得了具有高效移植能力的iHSPC，被同行高度评价，但同时也观察到其具有致瘤性，并发现致瘤突变呈现移植早期以点突变、晚期以易位突变为主的特点，并且在体内始终存在部分正常造血。基于此我们提出iHSPC部分衰老的亚克隆应对复制应激的能力减弱从而导致iHSPC基因组不稳定继而致瘤的假说，并拟从以下三方面进行研究：1.iHSPC发生衰老的阶段及条件；2.复制应激对iHSPC的影响；3.干预衰老、复制应激，对iHSPC致瘤性的影响。上述研究将使我们进一步了解iHSPC致瘤性的产生机制，继而为将来制备既具有高效移植能力又安全不致瘤的iHSPC提供理论指导。

Hematopoietic stem cells are in great demand in the clinic, but their source is very limited. To acquire transplantable hematopoietic stem and progenitor cells (HSPCs) derived from human induced pluripotent stem cells (iPSCs), the so-called iHSPCs, is a research hotspot as well as a great challenge in the field of hematology. So far, there have been very few successful reports worldwidely, but the methods are quite complicated and inefficient. We have previously obtained highly transplantable iHSPCs by using a single factor, MLL-AF4, which was highly evaluated by peers. Meanwhile, we also observed the tumorigenicity of these MLL-AF4 induced iHSPCs, and found that the leukemogenic point mutations mainly occurred during the early phase after transplantation, while the translocations mainly occurred during the late phase. However, despite of the malignant transformation, a small part of normal hematopoiesis always existed in the mice. Based on this, we propose the hypothesis that some subclones consisting of ageing iHSPCs may have decreased ability to respond to the replication stress imposed by the transplantation, which may lead to the genome instability and finally to the tumorigenic mutations. To test this hypothesis, we will carry out the research from the following three aspects: 1. The stage and condition for the occurrence of aging of iHSPC; 2. The effect of replication stress on iHSPC; 3. The effect on the tumorigenicity of iHSPC when intervening its aging and replication stress response. These studies will enable us to further understand the underlying mechanisms of the tumorigenicity of iHSPCs, and then provide theoretical guidance for the future preparation of iHSPC with high efficiency of transplantation but without tumorigenicity.