Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis

作者：Na Liu, Junhong Song, Yangyang Xie, Xiaolin Wang, Bowen Rong, Na Man, Meng-Meng Zhang, Qunling Zhang, Fei-Fei Gao, Meirong Du, Ying Zhang, Jian Shen, Chunhui Xu, Cheng-Long Hu, Jichuan Wu, Ping Liu, Yuan-Liang Zhang, Yin-Yin Xie, Ping Liu, Jinyan Huang, Qiuhua Huang, Fei Lan, Shuhong Shen, Stephen D. Nimer, Zhu Chen, Sai‐Juan Chen, Robert G. Roeder, Lan Wang, Xiao‐Jian Sun · 发表于：Proceedings of the National Academy of Sciences · 年份：2018 · DOI：10.1073/pnas.1809327116 · 被引用次数：24 · 研究领域：Acute Myeloid Leukemia Research、Protein Degradation and Inhibitors、Retinoids in leukemia and cellular processes

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 a...