自噬相关蛋白Atg3调控自噬性细胞死亡参与骨髓增生异常综合征向急性髓系白血病转化及miRNA靶向作用的初步探索

Myelodysplastic syndrome (MDS) is a group of heterogeneous hematopoietic stem cell malignancies with a high risk of transformation into acute myeloid leukemia (AML). Approximately 20% to 30% MDS patients progress to AML who have a poor prognosis. The molecular mechanisms of this transformation are not clear. Studies have shown that monoclonal hematopoietic malignant cells have reduced cell death and increased cell proliferation in the process of the transformation. Autophagic cell death is a different type of programmed cell death from apoptosis. Our previous findings showed that Atg3 was significantly downregulated in MDS patients with leukemic evolution, which confirmed that Atg3 might be a tumor suppressor gene and a potential therapeutic target of the transformation. However, it is unclear whether Atg3 plays a role in the transformation by modulating autophagic cell death and the upstream miRNA regulatory mechanisms are also not obvious. Based on our previous gene expression microarray, we focus on Atg3 in order to explore the role of autophagic cell death in the disease transformation from different aspects of cells, animal models and patients. Besides, we explore the upstream miRNA regulatory mechanisms. The present study will help understand the role of autophagy pathway in the process of transformation and provide new approaches to prevention of AML transformation.

骨髓增生异常综合征（MDS）是一组恶性克隆性造血干祖细胞疾病，大约20%-30%的MDS患者在病程中向急性髓系白血病（AML）转化，预后极差。研究表明，在MDS向AML转化过程中，恶性单克隆细胞死亡减少、异常增殖。然而，MDS向AML转化的分子机制并不清楚。自噬性细胞死亡是不同于凋亡的一种程序性细胞死亡方式。我们前期的研究结果发现，在MDS向急性白血病进展的过程中，自噬相关蛋白Atg3表达下调，提示Atg3可能起着抑癌作用，是MDS向AML转化的潜在治疗靶点。但是Atg3是否通过调控自噬性细胞死亡参与疾病进展及其miRNA调控机制并不明确。本研究立足于前期基因芯片的结果，以Atg3为研究的切入点，从细胞、动物模型和患者三个层面对自噬在MDS向AML转化中的作用进行探讨，并对其miRNA调控机制进行初步探索，结果将有助于正确理解自噬在MDS转白中的作用，有望为干预MDS转白提供新的手段。

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