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

Abstract

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.

• Authors: Na Liu, Junhong Song, Yangyang Xie, Xiao-Lin Wang, Bowen Rong, Na Man, Meng-Meng Zhang, Qunling Zhang, Fei-Fei Gao, Mei-Rong Du, Ying Zhang, Jian Shen, Chun-Hui Xu, Cheng-Long Hu, Ji-Chuan Wu, Ping Liu, Yuan-Liang Zhang, Yin-Yin Xie, Ping Liu, Jin-Yan Huang, Qiu-Hua Huang, Fei Lan, Shuhong Shen, Stephen D Nimer, Zhu Chen, Sai-Juan Chen, Robert G Roeder, Lan Wang, Xiao-Jian Sun
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 3 Pg. 890-899 (01 15 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 30593567 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AML1-ETO fusion protein, human
• Basic Helix-Loop-Helix Transcription Factors
• Core Binding Factor Alpha 2 Subunit
• Oncogene Proteins, Fusion
• RUNX1 Translocation Partner 1 Protein
• TCF3 protein, human
• TCF7L2 protein, human
• Transcription Factor 7-Like 2 Protein
• TCF12 protein, human

Topics

• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cell Differentiation
• Cell Line, Tumor
• Core Binding Factor Alpha 2 Subunit (metabolism)
• Humans
• Leukemia, Myeloid, Acute (etiology, metabolism)
• Oncogene Proteins, Fusion (metabolism)
• RUNX1 Translocation Partner 1 Protein (metabolism)
• Recurrence
• Transcription Factor 7-Like 2 Protein (metabolism)