TP53错义突变在骨髓增殖性肿瘤白血病转化中的作用机制及治疗新策略的研究

TP53突变是慢性期BCR-ABL阴性骨髓增殖性肿瘤（MPN）发生白血病转化（LT）的独立危险因素。在LT患者中其发生率约20%, 以错义突变最为常见。目前尚无直接证据证明TP53错义突变是否导致MPN-LT的发生。TP53错义突变不仅导致p53功能缺失，同时突变型p53可能获得了新功能，促进了肿瘤的发生和进展。我们推测TP53错义突变对于MPN干细胞功能的影响不同于TP53缺失，可能导致不同程度的疾病进展，甚至LT。因此，本课题以MPN中最常见TP53R175H和TP53R273H为切入点，建立伴有不同TP53突变的JAK2V617F/+小鼠模型。明确TP53错义突变能否促进LT及其与TP53缺失型JAK2V617F/+小鼠表型和分子机制之间的异同。基于小鼠模型，筛选新的治疗方案，评估常规治疗的潜在风险。本研究将加深我们对于TP53突变所致MPN-LT机制的理解和针对此类疾病的药物研发。

TP53 mutation is an independent risk factor for leukemic transformation (LT) in chronic-phase myeloproliferative neoplasms (MPN). In patients with MPN-LT, about 20% have TP53 mutations. Missense mutations are most common. At present, there was no direct proof indicating TP53 missense mutations relative to LT in MPN. Missense mutations not only result in the loss of function of p53, but also make the mutant p53 acquire some new functions which induce the development of cancer. It is hypothesized that TP53 missense mutations have different effect on MPN stem cells compared to TP53 deletions and missense mutations may associate with different level of progression, even LT. Therefore, this study will set up murine model with both JAK2V617F and hemizygous or heterozygous TP53R175H or R273H which are the most common in patients. It is expected that this study could illuminate whether missense mutations of TP53 can induce LT or not and the differences in phenotype and molecular mechanisms between missense mutations and delete mutations. Drug screening will be performed based on the murine model to look for new effective drug and to evaluate potetial LT risk when using regular drug in chronic phase . Collectively, this study will help us to know the association between TP53 mutations and MPN-LT and find some novel treatment strategies.