期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 3, 页码 890-899出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1809327116
关键词
AML1-ETO; E protein; AETFC; acute myeloid leukemia; dendritic cell
资金
- National Key Research and Development Plan of China [2018YFA0107802, 2018YFA0107202, 2016YFC0902202]
- Chinese Academy of Sciences (CAS) Bureau of Frontier Sciences and Education Program [QYZDBSSW-SMC027]
- National Natural Science Foundation of China (NSFC) General Program [81470316, 81670094, 81470334, 81670122, 81270623]
- NSFC Excellent Young Scholar Program [81622003]
- Chinese National Key Basic Research Project [2013CB966801]
- NIH R01 Grants [CA163086, CA178765, CA166835]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine [20152506]
- CAS Bureau of Major RD Program [XDA12010310]
- Shanghai Pudong Innovation Fund [PDJ2014-04]
- fourth round of Three-Year Public Health Action Plan [GWIV-25]
- Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]
- 111 Project [B17029]
- Samuel Waxman Cancer Research Foundation
- 1000 Talents Program for Young Scholars
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.
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