表观遗传学基因突变和表观遗传学图谱异常在急性髓性白血病中十分常见，而它们的生物学功能还不清楚。H3K4甲基转移酶MLL3及与之相结合的H3K27去甲基化酶UTX在白血病中缺失或突变。我们已阐明MLL3的单倍剂量不足能与p53和NF1缺失协同促进白血病的生成（第一作者，Cancer Cell 2014)。本研究中我们将通过shRNA干扰、CRISPR/Cas9基因编辑及小鼠基因工程等多种手段研究UTX缺失对造血干细胞的自我更新及急性髓性白血病发生的作用及分子机理。UTX的作用位点H3K27也在多种肿瘤中突变（H3K27M）。因而我们也将进一步研究H3K27M在造血干细胞的自我更新及急性髓性白血病发生的作用，并与UTX缺失对比，以期找到其共同作用机理。预期我们的研究将阐明H3K27甲基化及相关酶UTX在急性髓性白血病中的作用及分子机理，并可能对针对这类表观遗传学变异的靶向治疗有所启示。

The mutations of epigenetic regulators and abnormalities of epigenetic pattern are very common in acute myeloid leukemia (AML), but their functional roles are not well understood. MLL3, a H3K4 mono- and di-methyltransferase, and its binding parter UTX, a H3K27 demethylase, are frequently lost or mutated in AML. We have demonstrated that MLL3 haploinsufficiency cooperates with p53 and NF1 loss to promote leukemia genesis (Chen, et al., Cancer Cell 2014). In this proposed study, we will study the role and molecular mechanism of UTX in the self-renewal of hematopoietic stem cells and AML genesis by multiple genetic strategies, including shRNA interference, CRISPR/Cas9 genomic editing and mouse genetic engineering. Because H3K27, the target of UTX, is also mutated in multiple human cancers, we will study the functional role of H3K27 mutant (H3K27M) in leukemia genesis. We expect to find out the common molecular mechanism of UTX deficiency and H3K27 mutation in AML. Our study will clarify the functional roles and molecular mechanism of H3K27 methylation and its enzyme UTX, which might shed light on target therapy on these epigenetic abnormalities in human cancer.