利用正常干细胞→MDS（白血病前期）干细胞→白血病干细胞这样一个肿瘤干细胞发生、演变自然病史模式，以MDS及AML常见分子生物学异常MLL-PTD及RUNX1突变为着眼点。在MLL-PTD knock-in小鼠骨髓细胞中表达不同类型RUNX1突变，构建移植鼠动物模型。通过供者细胞植入分析、移植鼠造血干细胞自我更新及增殖能力分析、生存曲线分析，比较不同类型RUNX1突变与MLL-PTD 协同作用，探讨MLL-PTD联合RUNX1突变在MDS发生及AML转化中的作用机制。并且通过microarray分析，明确关键靶基因，为后续靶向治疗提供重要基础依据。

Myelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trilineage dysplasia and susceptibility to acute myelogenous leukemia (AML). Recently, mutations of the transcription factor RUNX1 and MLL-PTD have been identified in 10% to 20% and 2.7% to 4.4% of MDS and MDS/AML. Herein, we hypothesize that RUNX1 mutations and MLL-PTD cooperation contribute to MDS genesis and AML transformation. Therefore, we perform mouse bone marrow transplantation (BMT) using Mll-PTD knock-in mouse bone marrow cells transduced with different type of RUNX1 mutants (RUNX1 D171N, N-terminal mutant; RUNX1 s291fs, C-termina mutant). Underwent BMT, transplanted mice will be monitored for long-term reconstitution of the mutant RUNX1 transduced HSC cells, abnormal stem cell biology and their potential MDS onset. Briefly, engraftment of donor-derived cell and phenotype of hematopoietic stem cell in transplanted mice are assessed monthly. To address the self-renewal in vivo, serial BMT are performed 4 months after primary BMT. Survival is estimated by using Kaplan-Meier survival curve. Gene express profile will be perform on LSK cells from Mll-PTD - RUNX1D171, Mll-PTD - RUNX1s291fs, WT-RUNX1 D171, WT- RUNX1 s291fs and Mll-PTD knock-in mice. The key genes involved in those mouse models will be confirmed. Our proposed study will generate new mouse models for potentially modeling human MDS. RUNX1 mutations cooperate with MLL-PTD might accelerate the disease onset. This will help for the future cooperate events studies and drug tests. The new models will provide us new tools to cross with other available mutant mice models, which are implicated in human MDS at second or third hits.