BCL11A启动子区在急性髓系白血病中的表达调控机制研究

Acute myeloid leukemia (AML) is a severe form of hematologic malignancy with generally poor prognosis. BCL11A has been demonstrated as a leukemia promoting gene in mouse models and most recently, in patients with myeloid leukemia. BCL11A dysregulation is associated with the development and progression of leukemia. However, it is unclear whether and how BCL11A expression is controlled. Our preliminary work has identified the authentic transcriptional start site of BCL11A, and its promoter region which contains CEBPa binding sites. We also found the correlation between abnormal expression of BCL11A and mutated CEBPA and DNMT3A. Together with other evidence, we hereby hypothesize that, in AML cells, CEBPA can bind HDAC3 to suppress BCL11A expression and affect myeloid differentation, deregulation of which may promote leukemogenesis. This study is designed to explore how BCL11A expression is regulated and affect leukemogenesis, by bioinformatic analysis, chromatin immunoprecipitation, reporter assay, mouse model and patient sample analyses. It is our expectation that outcomes of this project will aid our understanding of BCL11A biology and AML with aberrant BCL11A expression, and possibly, improve clinical diagnosis and treatment of AML.

急性髓系白血病病因尚未完全清楚，治愈率低下。BCL11A是我们首先在小鼠中证明的白血病相关基因。近来我们发现BCL11A mRNA水平的异常改变，与患者白血病的发生发展密切相关。那么，BCL11A的表达调控机制就成为一个领域发展需求驱动的重要科学问题。前期研究中我们发现了BCL11A新的转录起始位点，确定了BCL11A启动子区，其中含有CEBPa的潜在结合位点；外源性表达CEBPa可抑制BCL11A的转录，而后者可抑制髓系细胞诱导分化；白血病人标本中BCL11A高表达与CEBPA和HDAC3突变相关。另文献报道CEBPa可结合HDAC3负调下游基因表达。我们提出假说认为：CEBPa可结合HDAC3抑制BCL11A的转录，进而影响髓系细胞分化；其失调可能参与白血病的发生发展。本申请项目拟探讨BCL11A表达调控机理，预期将有助于加深对白血病分子机制的认识，可能改善白血病的临床诊疗。

根据设计书的计划要点，我们的研究内容按照计划逐步实施，但对研究重点方面有所侧重。我们继续扩大收集了临床白血病病人骨髓和外周血标本，进行实验系统的建立、测试、控制和完善，并获取大部分的基础数据。同时采用5’RACE 等技术确定BCL11A在多种AML细胞系和病人标本中的转录起始位点，进行生物信息学分析；采用诱导分化细胞培养模型，研究内源性CEBPA与BCL11A mRNA表达水平之间关联性，另外我们还在研究过程中应用了纳米以及磁珠分离等技术，初步探讨了纳米技术在白血病研究中的应用，推动与白血病相关科学问题和临床问题的研究进程，这些新增内容使我们的研究更具新颖性和挑战性。