FLT3调控异常在t(8;21)白血病异质性中的影响及其分子机制研究

Acute myeloid leukemia is the most frequently occurring leukemia in China, in which t(8;21) is the most commonly found recurrent chromosome translocation. This translocation leads to the featured fusion gene of AML1/ETO. Although most of the patients respond well to the induction therapy at early stage, the prognosis of this group is still heterogeneous, with the molecular mechanism remains unknown. In our preliminary research, we found that the expression of FLT3 was always upregulated in t(8;21) patient samples, which did not parallel well with the expression of AML1/ETO gene. The overexpression of FLT3 might facilitate the deregulation of its own signal pathway, as well as influence (or change) the methylation style of several target genes downstream of AML1/ETO, possibly involving CCND3, CDK4, CEBPα, Pu.1, ABCB4 and ABCG2, respectively. This might lead to the deregulation of cell cycle progression, cell differentiation and multi-drug resistance. Further disclosing the mechanism of this regulation network may help to understand more of this disease, and may hopefully help to employ new prognostic evaluation markers or potential therapeutic targets in the diagnosis or treatment of this disease.

急性髓细胞性白血病在我国是发病率最高的一组白血病，其中t(8;21)染色体易位是最常见的一种可重现性遗传学改变。该易位的特征性产物是AML1/ETO融合基因。近年来临床诊治中发现t(8;21)白血病的预后异质性较大，给治疗策略的合理选择带来不少困惑。造成这种异质性的分子机制尚不明确。我们在前期研究中发现，FLT3基因表达在t(8;21)白血病细胞中常增高，而且与AML1/ETO的表达增高不完全平行。FLT3基因的高表达有可能促使其自身信号通路异常活化、并有可能通过改变AML1/ETO对下游基因的甲基化调控模式进而导致CCND3、CDK4等细胞周期因子、CEBPα、Pu.1等细胞分化因子、以及ABCB4、ABCG2等多药耐药基因的调控异常。进一步深入研究将有助于揭示导致t(8;21)白血病异质性和预后不良的分子机制，为完善该类疾病的预后分层体系和探索新的分子治疗靶点提供有力的理论依据。

急性髓细胞性白血病在我国是发病率最高的一组白血病，其中t(8;21)染色体易位是最常见的一种可重现性遗传学改变，该易位的特征性产物是AML1/ETO融合基因。近年来临床诊治中发现t(8;21)白血病的预后异质性较大，给治疗策略的合理选择带来不少困惑。造成这种异质性的分子机制尚不明确。我们的研究发现，FLT3基因表达在t(8;21)白血病细胞中常增高，而且其表达增高与AML1/ETO的表达增高并不平行，说明FLT3基因表达在t(8;21)白血病中存在较大异质性；在进一步的临床预后分析中，我们将FLT3基因表达水平大于35％者归为高表达组，表达水平低于35％者归为低表达组，结果发现FLT3高表达组患者的复发率及死亡率较低表达组有很明显的差异趋势，提示FLT3基因高表达可能是t(8;21)白血病预后不良的独立预后因素之一；通过分子机制研究，我们发现FLT3与AML1/ETO融合基因有可能通过协同作用影响JAK/STAT信号通路中STAT5蛋白的磷酸化，从而影响该通路下游的细胞周期或细胞分化基因的表达，该机制可能是影响此类白血病发生发展及预后的重要分子机制之一。本研究结果为此类白血病的预后分层以及开发新的靶向治疗手段提供了理论依据。