慢性髓性白血病微泡多重定向调控造血干/祖细胞促疾病进展

项目名称： 慢性髓性白血病微泡多重定向调控造血干/祖细胞促疾病进展

项目编号： No.81470333

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 游泳

作者单位： 华中科技大学

项目金额： 70万元

中文摘要： 慢性髓性白血病(CML)如何由相对惰性向预后极差的进展期演变仍不明了，近来发现白血病状态重编程造血干/祖细胞(HSPC)是CML进展的关键机制。通过前一个项目的研究，我们发现CML细胞分泌的微泡(MV)携带疾病中枢分子BCR-ABL1，并能够体外恶性转化HSPC；同时，从MV切入符合CML进展的疾病特点。由此我们推测：MV介导了CML状态对HSPC的恶性转化，参与疾病进展。本课题拟在前期研究基础上，通过体内外实验及临床研究进一步证明MV参与CML向急性白血病转化；明确MV转化的确切细胞组分，证明其通过投递外源性RNA发挥效应，并初步阐明HSPC白血病化的分子机制；此外，研究不同CML-MV中miRNA的表达差异及组装机制。本项目的完成，将有助于发现CML疾病进展及其异质性的新机制，MV可望发展为CML进展的早期预警信号及关键阻遏靶标；同时本课题还为研究白血病发生提供了一种极佳的模型选择。

中文关键词： 微泡；微小RNA；造血干/祖细胞；慢性髓性白血病

英文摘要： Chronic myeloid leukemia (CML) is a clonal malignant disorder of a pluripotent hematopoietic stem cell characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), which generates the Philadelphia (Ph) chromosome. CML represents an important paradigm for understanding the molecular evolution of cancer because it was the first cancer shown to be initiated at the hematopoietic stem cell level by BCR-ABL1; and the first cancer found to undergo blastic transformation. Notwithstanding the remarkable success in treating patients in CML-CP with ABL1 kinase inhibitors such as imatinib, the dismal outcome of blast crisis (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the disease progression. Besides, diagnostic and therapeutic strategies that predict and prevent CML progression represent compelling unmet medical needs. It has been reported that during myelogenous blast crisis, abnormal granulocyte macrophage progenitors (GMP) acquired self-renewal potential and function as leukemic stem cells; and the acute lymphoblastic leukemia (ALL)-initiating cells may result from B-lymphoid progenitors. However, the precise molecular mechanisms driving malignant reprogramming of progenitors into LSC in BC CML have remained elusive. Microvesicles (MV), also termed to as microparticles, have been described as a new and important mechanism of intercellular signal communication via fusing with the plasma membrane of the target cell and discharging their cargo into the cytosol. By facilitating the horizontal transfer of bioactive molecules such as proteins, RNAs and microRNAs, MVs are now thought to have vital roles in tumor invasion and metastases, inflammation, coagulation, stem-cell renewal and transformation of healthy cells. We have demonstrated that BCR-ABL1-positive MVs could initiate malignant transformation of hematopoietic stem/progenitor cells (Leukemia, 2014, doi:10.1038/leu.2014.51). The aim of this subject is to investigate whether MV plays a role in the transformation of blast crisis. In this subject, clinical observation and mice models will be performed to prove that MV participates in the crisis transformation of CML. Besides, we will figure out the key recipient cell of leukemogenesis and the mechanisms that lead to the leukemia transformation induced by MV; as well as compounds in MV that could alter the transformation. Findings of this subject will sheed much-needed light on molecular mechanisms driving malignant reprogramming of progenitors into LSC in BC CML. It also presented a unique opportunity to prospectively study the changes undergone by progenitors, leading to their malignant transformation, serving as a convenient and operable model for investigating leukemogenesis.

英文关键词： microvesicles;microRNA;hematopoietic stem/progenitor cells;chronic myeloid leukemia