AML造血干细胞移植后复发和白血病干细胞增殖动力学变化的相关性及其机制

异基因造血干细胞移植是治愈急性白血病的重要手段，但多年来复发率居高不下，是移植失败的主要原因。多项研究提示白血病干细胞（LSC）是白血病发生、发展和复发的关键细胞，是移植后复发的根源。我们的前期研究表明，化疗后白血病细胞与正常造血干/祖细胞的增殖差异及以"LSC"界定的微小残留白血病水平与疾病复发密切相关。本课题拟应用携带特定遗传和表面标记的白血病移植后复发的动物模型，研究急性髓细胞白血病的LSC在移植前、后和白血病复发过程中生物学特性尤其是细胞增殖调控的变化，并与正常造血干/祖细胞比较，以评价移植预处理和供体免疫效应细胞对LSC细胞周期调控和增殖动力学的影响，阐明移植后白血病复发和LSC增殖动力学等生物学特性改变的相关性，并利用高通量生物信息学技术筛选可干预的关键分子进行干预，为深入理解移植后白血病复发的机制，探索干预策略提供新的思路。

Acute leukemia can be cured by allogenetic hematopoietic stem cell transplantation (allo-HSCT), but relapse of the disease remains to be a major cause of treatment failure. It is accepted that leukemia stem cells (LSC) are the key cells in the initiation, progression and recurrence of leukemias, and the origin of relapse post allo-HSCT. Our previous observation suggested that relapse is closely associated with proliferative discrepancies between leukemic cells and hematopoietic stem cells and the level of minimal residual leukemia defined by LSC. In the present project, we propose to investigate the biological characteristics, especially proliferative capacities of LSCs, in comparison with that of normal hematopoietic stem cells, in response to preconditioning intensive chemo- and/or radiotherapy as well as to donor derived immune effector cells and during relapse of the disease, by using murine models of acute myeloid leukemia carrying specific genetic and surface markers. The mechanisms of cell cycle control and kinetics of LSC proliferation before and after transplant and during the process of leukemia relapse will be further studied, with the aim to identify the key genes and signal pathways by means of high-through and bioinformatics techoniques. We believe that these studies will provide key information about, and new insights into, the mechanisms and new strategies for prevention and treatment of post transplantation leukemia relapse.