Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):890-899. doi: 10.1073/pnas.1809327116. Epub 2018 Dec 28.
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, , 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.
AML1-ETO 融合蛋白由 t(8;21)染色体易位产生，几乎涉及 20%的急性髓系白血病 (AML)病例。在白血病细胞中，AML1-ETO 存在于并通过稳定的蛋白质复合物 AML1-ETO 包含的转录因子复合物 (AETFC) 发挥作用，该复合物包含多个转录 (共) 因子。在这些 AETFC 成分中，HEB 和 E2A 是广泛表达的 E 蛋白的两个成员，它们直接与 AML1-ETO 相互作用，赋予 AETFC 新的 DNA 结合能力，并且对白血病的发生是必不可少的。然而，第三个 E 蛋白 E2-2 在表达 AML1-ETO 的白血病细胞中特异性沉默，表明 E2-2 是白血病发生的负调控因子。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，并且这种抑制需要 bHLH DNA 结合结构域。RNA-seq 和 ChIP-seq 分析表明，尽管有一些重叠，但这三种 E 蛋白差异调节许多靶基因。特别是，研究表明 E2-2 不仅将 AETFC 重新分布到与树突状细胞分化相关的一些基因上，而且还激活了这些基因，并抑制了 MYC 靶基因。在 AML 患者中，t(8;21)亚型中 E2-2 的表达相对较低，并且鉴定出 E2-2 的一个靶基因 作为复发的潜在预测因子。在人类 t(8;21)白血病的小鼠模型中，E2-2 的抑制加速了白血病的发生。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 不同，E2-2 损害了 AETFC 的功能并负调控白血病的发生。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的确切机制的理解，并有助于开发诊断/治疗策略。
