ZFX（Zinc finger protein, X-linked）是维持多种干细胞生存和干性（stemness）的锌指蛋白。慢性髓细胞白血病（CML）干细胞是疾病维持和复发的重要因素。预研发现患者CD34+细胞（包括静息期亚群）中ZFX异常高表达；沉默ZFX抑制患者CD34+细胞生长并增强其伊马替尼（IM）敏感性。因此亟待研究ZFX在CML干细胞生长、干性维持及IM敏感性中的作用。本项目将检测沉默或过表达ZFX对CML干细胞（CD34+CD38-LI1RAP+）的长期培养起始细胞（LTC-IC）、免疫缺陷小鼠（NOD/SCID）移植能力和IM敏感性的影响；通过Microarray、染色质免疫共沉淀（ChIP）和凝胶迁移（EMSA）等鉴定ZFX的靶基因，并证实ZFX与其靶基因间的功能拮抗关系。将首次揭示ZFX在CML干细胞中的作用，增进CML致病机制的认识，有望为改善CML治疗提供新策略。

Zinc finger gene ZFX has been identified as a key regulator of both embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs) for their survival and maintenance of stemness. Several reports have demonstrated that Zfx is aberrantly expressed in various human tumors and implicated in their survival and growth, but its role in human hematological malignancies remains unclear. Chronic myeloid leukemia (CML) originates from normal HSCs acquiring BCR-ABL fusion gene. The CML stem cell is the key for the disease maintenance and relapse. However, the expression and function of ZFX in CML stem cells have not been addressed yet. In our study, we first found that ZFX was up-regulated in the CD34+ cells (including the quiescent subset) from CML patients in comparison to the normal control cells. ZFX silence inhibited the proliferation of leukemic CD34+ cells and impaired their colony-forming cell (CFC) capacities as well. Interestingly, ZFX silence sensitized CD34+ CML cells (both IM sensitive and insensitive samples) to the treatment of IM. We propose to assess the effects of ZFX silence or overexpression in CML stem cells (CD34+CD38-IL1RAP+) on their capacities of LTC-IC (long-term culture initiating-cell), IM sensitivity and xenoengraftment in NOD/SCID mice. In order to identify critical functional targets and regulatory network of ZFX in these cells, microarray, chromatin immunoprecipitate (ChIP) and electrophoretic mobility shift assay (EMSA) will be utilized. It would be the first report to delineate the role of ZFX in CML stem cells, which will deepen the understanding of CML pathology and potentially provide valuable clues for novel therapies against this disease.