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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (4) : 285-304     DOI: 10.1007/s11515-016-1415-1
New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins
Jian Li,Chun Guo,Nickolas Steinauer,Jinsong Zhang()
Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA
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BACKGROUND: Nearly 15% of acute myeloid leukemia (AML) cases are caused by aberrant expression of AML1-ETO, a fusion protein generated by the t(8;21) chromosomal translocation. Since its discovery, AML1-ETO has served as a prototype to understand how leukemia fusion proteins deregulate transcription to promote leukemogenesis. Another leukemia fusion protein, E2A-Pbx1, generated by the t(1;19) translocation, is involved in acute lymphoblastic leukemias (ALLs). While AML1-ETO and E2A-Pbx1 are structurally unrelated fusion proteins, we have recently shown that a common axis, the ETO/E-protein interaction, is involved in the regulation of both fusion proteins, underscoring the importance of studying protein–protein interactions in elucidating the mechanisms of leukemia fusion proteins.

OBJECTIVE: In this review, we aim to summarize these new developments while also providing a historic overview of the related early studies.

METHODS: A total of 218 publications were reviewed in this article, a majority of which were published after 2004. We also downloaded 3D structures of AML1-ETO domains from Protein Data Bank and provided a systematic summary of their structures.

RESULTS: By reviewing the literature, we summarized early and recent findings on AML1-ETO, including its protein–protein interactions, transcriptional and leukemogenic mechanisms, as well as the recently reported involvement of ETO family corepressors in regulating the function of E2A-Pbx1.

CONCLUSION: While the recent development in genomic and structural studies has clearly demonstrated that the fusion proteins function by directly regulating transcription, a further understanding of the underlying mechanisms, including crosstalk with other transcription factors and cofactors, and the protein–protein interactions in the context of native proteins, may be necessary for the development of highly targeted drugs for leukemia therapy.

Keywords AML1-ETO      E2A-Pbx1      E-proteins      chromosomal translocation      transcription      leukemia     
Corresponding Authors: Jinsong Zhang   
Just Accepted Date: 18 July 2016   Online First Date: 10 August 2016    Issue Date: 30 August 2016
 Cite this article:   
Jian Li,Chun Guo,Nickolas Steinauer, et al. New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins[J]. Front. Biol., 2016, 11(4): 285-304.
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Jian Li
Chun Guo
Nickolas Steinauer
Jinsong Zhang
Fig.1  Schematic representations of domain organization of AML1-ETO, E2A-Pbx1, and the related wild-type proteins. RHD: runt homology domain. NHR1-4: nervy homology regions 1-4. NHR1 and NHR4 are also known as TAFH and MYND zinc fingers, respectively. AD1 and AD2: activation domains 1 and 2. DES: downstream ETO-interacting sequences, which includes a minimal binding sub-region named NHR2 binding (N2B) motif. HD: homeobox domain. bHLH: basic helix-loop-helix domain. The vertical dash lines depict the breakpoints during chromosomal translocation.
Fig.2  Domains of AML1-ETO and their interacting proteins. Biochemical studies have identified an array of AML1-ETO-interacting proteins, many of which bind to the conserved RHD and NHR domains of AML1 and ETO, respectively. Proteins bound to RHD include: CBFb (Meyers et al., 1995), AML1(Li et al., 2015a), C/EBPa (Zhang et al., 1996), C/EBPb (Tahirov et al., 2001), GATA1 (Elagib et al., 2003), Ets1 (Kim et al., 1999; Shrivastava et al., 2014; Shiina et al., 2015), PU.1 (Petrovick et al., 1998), MEF (Mao et al., 1999), LEF1 (Li et al., 2004), c-FOS/c-JUN(D’Alonzo et al., 2002), BSAP/PAX5 (Libermann et al., 1999), SMAD3(Jakubowiak et al., 2000), Sp1 (Wei et al., 2008). Some of the transcription factors may interact with AML1-ETO indirectly through the proximal binding sites on target DNA. Proteins bound to the ETO portion of the fusion protein include: Atrophin-1 (Wood et al., 2000), Dnmt1 (Liu et al., 2005), SHARP (Salat et al., 2008), JMJD1c (Chen et al., 2015), PLZF (Melnick et al., 2000), Bcl6 (Chevallier et al., 2004), HEB/E2A/LYL1/LMO2/Ldb1(Sun et al., 2013), Gfi1 (McGhee et al., 2003), corepressors NCoR/SMRT/HDAC3, mSin3A/HDAC1/2 (Gelmetti et al., 1998; Lutterbach et al., 1998b; Wang et al., 1998; Amann et al., 2001; Hildebrand et al., 2001; Zhang et al., 2001), p300 (Wang et al., 2011a), HSP90 (Komori et al., 1999), ETO-2/MTGR1 (Kitabayashi et al., 1998; Liu et al., 2006), PKA(RIIa) (Fukuyama et al., 2001), and SON (Ahn et al., 2008). PRMT1 binds to AML1-ETO9a fragment (Shia et al., 2012). In addition to the reported binary interactions, proteome-scale mapping of the human interactome network further showed that ETO interacts with EPS8, MEOX2, STX11, ZMYM4, LPXN, HOMER3, SPRY2, MID2, GSE1, ABI3, TAF9B, WBP11, NECAB2, PRDM14, C19orf57, CPSF7, EFHC2, LZTS2, CREB3L1, SPERT, TRIM42, CCDC36, CEP170P1 (Rual et al., 2005; Rolland et al., 2014). Proteins that have been shown to involve direct interactions are highlighted in dark red.
Repression Molecular/Biological functions References
C/EBPa Transcription factor, myeloid differentiation Pabst et al., 2001
PIRIN Transcription factor, myeloid differentiation Licciulli et al., 2010
P14 (ARF) Tumor suppressor Linggi et al., 2002
Neurofibromatosis-1 Tumor suppressor Yang et al., 2005
RASSF2 Tumor suppressor Samuel A Stoner, 2013
CD45 Negative regulator of JAK/STAT signaling Lo et al., 2012
Cathepsin G Protease, AML1-ETO degradation Jin et al., 2013
OGG1 DNA repair Alcalay et al., 2003
Activation Molecular/Biological functions References
JUP(g-Catenin) Wnt/b-Catenin signaling Muller-Tidow et al., 2004; Zheng et al., 2004; Tonks et al., 2007
JAGGED1 Notch signaling Alcalay et al., 2003
TRKA Nerve Growth Factor receptor Mulloy et al., 2005
ID1 Maintains HSC self-renewal Jankovic et al., 2007
P21/WAF1 HSC self-renewal Peterson et al., 2007
PONTIN Cell cycle progression Breig et al., 2014
BCL2 Apoptosis inhibitor Klampfer et al., 1996
BCL-xl Apoptosis inhibitor Chou et al., 2012
Tab.1  List of representative AML1-ETO target genes
Fig.3  ETO and E-protein interactions. Schematic representations showing domain structures of ETO and E-proteins, along with the three binding interfaces: NHR1/AD1, NHR2/DES and NHR1/DES (Guo et al., 2009). DES harbors the minimal sub-region that shows binding to NHR2 (N2B).
Fig.4  Differential involvement of ETO-corepressor/E-protein interactions in distinct leukemogenic pathways. (A) Alignment of PCET sequences from HEB, E2-2 and E2A. E2A-specific change is labeled with yellow stars. (B) In t(8;21) AML, strong AML1-ETO/E-protein (HEB or E2A) interactions facilitate transcriptional repression to promote leukemogenesis. (C) In t(1;19) ALL, due to E2A-specific amino-acid changes flanking the PCET motif, the binding affinity of E2A-Pbx1 to ETO-2/MTGR1 corepressors is reduced. As a result, E2A-Pbx1 is skewed toward recruiting p300/CBP HATs for gene activation.
Domain Structure description PDB number References
RHD RHD 1CO1, 1LJM, 1CMO Berardi et al., 1999; Nagata et al., 1999; Bartfeld et al., 2002
RHD+ DNA 1HJC Tahirov et al., 2001
RHD+ CBFb + C/EBPb + DNA 1IO4 Tahirov et al., 2001
RHD+ CBFb + DNA 1H9D Bravo et al., 2001
RHD+ CBFb 1E50 Warren et al., 2000
NHR1(eTAFH) NHR1 2H7B Plevin et al., 2006
NHR1 (F136Y) 2PP4 Wei et al., 2007
NHR1+ HEB-PCET 2KNH Park et al., 2009a
NHR2 NHR2 1WQ6 Liu et al., 2006
NHR2+ HEB-N2B 4JOL Sun et al., 2013
NHR3 NHR3+ PKA(RIIa) 2KYG Corpora et al., 2010
NHR4 NHR4 2OD1 Liu et al., 2007
NHR4+ SMRT 2ODD Liu et al., 2007
dTAFH TAF4-TAFH 2P6V Wang et al., 2007
Tab.2  Reported 3D structures of AML1-ETO domains
Fig.5  3D models of AML1-ETO and its complexes with binding partners. Available 3D structures of isolated AML1-ETO domains are shown by PyMOL and the structures were connected with dashed lines. RHD is colored in blue, its binding partner CBFb in cyan, NHR1 in green, NHR2 in orange, NHR3 in hot pink, and NHR4 in red. For ETO binding partners, HEB peptides are in yellow, PKA (RIIa) in gray, and SMRT peptide in pale cyan. Note that NHR2 mediates tetramerization of AML1-ETO proteins (the other three NHR2 domains are in gray), thus bridging 4 copies of each interacting proteins. AML-ETO can also form hetero-oligomers with ETO family proteins (ETO-2, MTGR1).
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