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

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 & 9 others Qiu Hua Huang, Fei Lan, Shuhong Shen, Stephen D Nimer, Zhu Chen, Sai Juan Chen, Robert G. Roeder, Lan Wang, Xiao Jian Sun

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)890-899
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number3
DOIs
StatePublished - Jan 15 2019

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Fusion Oncogene Proteins
Core Binding Factor Alpha 2 Subunit
Transcription Factor 7-Like 2 Protein
Basic Helix-Loop-Helix Transcription Factors
Tumor Cell Line
Acute Myeloid Leukemia
Dendritic Cells
Cell Differentiation
Leukemia
Transcription Factors
Recurrence
Proteins
Genes
Genetic Translocation
DNA

Keywords

  • Acute myeloid leukemia
  • AETFC
  • AML1-ETO
  • Dendritic cell
  • E protein

ASJC Scopus subject areas

  • General

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 3, 15.01.2019, p. 890-899.

Research output: Contribution to journalArticle

Liu, N, Song, J, Xie, Y, Wang, XL, Rong, B, Man, N, Zhang, MM, Zhang, Q, Gao, FF, Du, MR, Zhang, Y, Shen, J, Xu, CH, Hu, CL, Wu, JC, Liu, P, Zhang, YL, Xie, YY, Liu, P, Huang, JY, Huang, QH, Lan, F, Shen, S, Nimer, SD, Chen, Z, Chen, SJ, Roeder, RG, Wang, L & Sun, XJ 2019, 'Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis' Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 3, pp. 890-899. https://doi.org/10.1073/pnas.1809327116
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 ; Liu, Ping ; 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. / Different roles of E proteins in t(8;21) leukemia : E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 3. pp. 890-899.
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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.",
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T1 - Different roles of E proteins in t(8;21) leukemia

T2 - E2-2 compromises the function of AETFC and negatively regulates leukemogenesis

AU - Liu, Na

AU - Song, Junhong

AU - Xie, Yangyang

AU - Wang, Xiao Lin

AU - Rong, Bowen

AU - Man, Na

AU - Zhang, Meng Meng

AU - Zhang, Qunling

AU - Gao, Fei Fei

AU - Du, Mei Rong

AU - Zhang, Ying

AU - Shen, Jian

AU - Xu, Chun Hui

AU - Hu, Cheng Long

AU - Wu, Ji Chuan

AU - Liu, Ping

AU - Zhang, Yuan Liang

AU - Xie, Yin Yin

AU - Liu, Ping

AU - Huang, Jin Yan

AU - Huang, Qiu Hua

AU - Lan, Fei

AU - Shen, Shuhong

AU - Nimer, Stephen D

AU - Chen, Zhu

AU - Chen, Sai Juan

AU - Roeder, Robert G.

AU - Wang, Lan

AU - Sun, Xiao Jian

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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.

AB - 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.

KW - Acute myeloid leukemia

KW - AETFC

KW - AML1-ETO

KW - Dendritic cell

KW - E protein

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