急性髓系白血病治愈率低且复发率高，严重危害人类健康。白血病干细胞的存在是造成白血病发生、发展和复发的根本原因。探索能够有效抑制白血病干细胞活性的分子靶点，有助于建立治疗白血病的新方法。申请者前期研究发现：碱性神经酰胺酶3（ACER3）在急性髓系白血病干细胞中高表达；ACER3表达水平与急性髓系白血病患者生存时间呈负相关。且神经酰胺累积可抑制急性髓系白血病细胞增殖，并诱导其凋亡。推测：ACER3可能通过调节神经酰胺代谢，进而调控急性髓系白血病干细胞的增殖和凋亡。本项目拟建立ACER3基因敲除细胞系及小鼠模型，探索ACER3在调控白血病干细胞活性和急性髓系白血病演进过程中的作用，并阐明其分子机制。这些研究有助于全面认识ACER3的生物学功能，具有重要的理论价值；同时，可以为开发治疗急性髓系白血病的新方法奠定理论基础，具有潜在的应用价值。

Acute myeloid leukemia (AML), characterized by the low cure rate and high relapse, is the most severe adult acute leukemia. Leukemia stem cells (LSCs) are considered as the source of leukemogenesis and development, are also the root cause for the treatment failure and relapse. Exploring the molecular targets involved in regulating activity of LSCs will promote the development of new strategies in eradicating AML. For the first time, we found that Alkaline Ceramidase 3 (ACER3) was highly expressed in some AML cell lines and AML stem cells. The ACER3 expression levels negatively correlate with survival of AML patients. Here we propose to test the hypothesis that ACER3 plays critical roles in regulation of activities of AML stem cells and development of AML. We will construct ACER3 knockdown AML cell linse by shRNA-encoding lentivirus system and employ the ACER3 knockout mouse model to study the regulatory role of ACER3 in self-renewal, differentiation and apoptosis of LSCs and dissect the underlying mechanism of signal transduction. Our studies will elucidate the function of ACER3 in regualation of AML development, and provide the basis for the development of novel therapeutics for AML treatment.