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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-01, Vol.116 (3), p.890-899
• Main Authors: Liu, Na, Song, Junhong, Xie, Yangyang, Wang, Xiao-Lin, Rong, Bowen, Man, Na, Zhang, Meng-Meng, Zhang, Qunling, Gao, Fei-Fei, Du, Mei-Rong, Zhang, Ying, Shen, Jian, Xu, Chun-Hui, Hu, Cheng-Long, Wu, Ji-Chuan, Liu, Ping, Zhang, Yuan-Liang, Xie, Yin-Yin, Huang, Jin-Yan, Huang, Qiu-Hua, Lan, Fei, Shen, Shuhong, Nimer, Stephen D., Chen, Zhu, Chen, Sai-Juan, Roeder, Robert G., Wang, Lan, Sun, Xiao-Jian, 孙晓建
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; AML1 protein; Basic Helix-Loop-Helix Transcription Factors - metabolism; Binding; Biological Sciences; Cell Differentiation; Cell Line, Tumor; Cells; Core Binding Factor Alpha 2 Subunit - metabolism; Dendritic cells; Deoxyribonucleic acid; Diagnostic systems; Differentiation (biology); DNA; E protein; Ectopic expression; Fusion protein; Gene expression; Genes; Heterogeneity; Humans; Leukemia; Leukemia, Myeloid, Acute - etiology; Leukemia, Myeloid, Acute - metabolism; Leukemogenesis; Medical treatment; Myc protein; Myeloid leukemia; Oncogene Proteins, Fusion - metabolism; PNAS Plus; Proteins; Recurrence; Ribonucleic acid; RNA; RUNX1 Translocation Partner 1 Protein - metabolism; Target recognition; Transcription Factor 7-Like 2 Protein - metabolism; Transcription factors; Translocation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1809327116

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.