Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis
Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis
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E 蛋白在 t(8;21) 白血病中的不同作用：E2-2 损害 AETFC 的功能并负向调节白血病发生。
DOI：
10.1073/pnas.1809327116
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发表时间：
2019-01-15
影响因子：
11.1
通讯作者：
Sun, Xiao-Jian
中科院分区：
文献类型：
--
作者：
Liu, Na;Song, Junhong;Sun, Xiao-Jian
由t(8;21)染色体易位产生的AML1 - ETO融合蛋白在近20%的急性髓系白血病（AML）病例中起因果作用。在白血病细胞中，AML1 - ETO存在于一个稳定的蛋白复合物——含AML1 - ETO的转录因子复合物（AETFC）中并通过其发挥作用，该复合物包含多种转录（辅）因子。在这些AETFC成分中，HEB和E2A这两种广泛表达的E蛋白成员直接与AML1 - ETO相互作用，赋予AETFC新的DNA结合能力，并且对白血病发生至关重要。然而，第三种E蛋白E2 - 2在表达AML1 - ETO的白血病细胞中特异性沉默，这表明E2 - 2是白血病发生的一个负向因子。事实上，E2 - 2的异位表达选择性地抑制表达AML1 - ETO的白血病细胞的生长，并且这种抑制作用需要bHLH DNA结合结构域。RNA - seq和ChIP - seq分析显示，尽管存在一些重叠，但这三种E蛋白对许多靶基因的调控存在差异。特别是，研究表明E2 - 2既将AETFC重新分布到一些与树突状细胞分化相关的基因上并激活它们，又抑制MYC靶基因。在AML患者中，E2 - 2在t(8;21)亚型中的表达相对较低，并且一个E2 - 2靶基因THPO被确定为复发的潜在预测因子。在人类t(8;21)白血病小鼠模型中，E2 - 2的抑制加速白血病发生。综上所述，这些结果表明，与促进AML1 - ETO介导的白血病发生的HEB和E2A相反，E2 - 2损害AETFC的功能并负向调控白血病发生。因此，这三种E蛋白定义了AETFC的异质性，这提高了我们对白血病发生精确机制的理解，并有助于诊断/治疗策略的开发。
The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8; 21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8; 21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.