Different roles of E proteins in t(8;21) leukemia : E2-2 compromises the function of AETFC and negatively regulates leukemogenesis
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 116(2019), 3 vom: 15. Jan., Seite 890-899 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Na [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.03.2019 Date Revised 29.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1809327116 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM292226675 |
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| 100 | 1 | |a Liu, Na |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Different roles of E proteins in t(8;21) leukemia |b E2-2 compromises the function of AETFC and negatively regulates leukemogenesis |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 13.03.2019 | ||
| 500 | |a Date Revised 29.04.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AETFC | |
| 650 | 4 | |a AML1-ETO | |
| 650 | 4 | |a E protein | |
| 650 | 4 | |a acute myeloid leukemia | |
| 650 | 4 | |a dendritic cell | |
| 650 | 7 | |a AML1-ETO fusion protein, human |2 NLM | |
| 650 | 7 | |a Basic Helix-Loop-Helix Transcription Factors |2 NLM | |
| 650 | 7 | |a Core Binding Factor Alpha 2 Subunit |2 NLM | |
| 650 | 7 | |a Oncogene Proteins, Fusion |2 NLM | |
| 650 | 7 | |a RUNX1 Translocation Partner 1 Protein |2 NLM | |
| 650 | 7 | |a TCF3 protein, human |2 NLM | |
| 650 | 7 | |a TCF7L2 protein, human |2 NLM | |
| 650 | 7 | |a Transcription Factor 7-Like 2 Protein |2 NLM | |
| 650 | 7 | |a TCF12 protein, human |2 NLM | |
| 650 | 7 | |a 142661-93-6 |2 NLM | |
| 700 | 1 | |a Song, Junhong |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Yangyang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiao-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Rong, Bowen |e verfasserin |4 aut | |
| 700 | 1 | |a Man, Na |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Meng-Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qunling |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Fei-Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Mei-Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Chun-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Cheng-Long |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Ji-Chuan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yuan-Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Yin-Yin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jin-Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Qiu-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Shuhong |e verfasserin |4 aut | |
| 700 | 1 | |a Nimer, Stephen D |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Sai-Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Roeder, Robert G |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xiao-Jian |e verfasserin |4 aut | |
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