Mtg16/Eto2 Contributes to Murine T-Cell Development

Hunt, Aubrey; Fischer, Melissa A.; Engel, Michael; Hiebert, Scott W.

doi:10.1128/mcb.01458-10

Cited by 28 publications

(46 citation statements)

References 49 publications

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“…The repression is thought to be important for the normal hematopoiesis and for the leukemogenic function of AML1-ETO (25,49–51). However, we found that, unlike HEB-AD1, the binding of E2A-AD1 to ETO is intrinsically weak.…”

Section: Resultsmentioning

confidence: 99%

Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways

Gow

Guo

Wang

et al. 2013

Nucleic Acids Research

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E2A is a member of the E-protein family of transcription factors. Previous studies have reported context-dependent regulation of E2A-dependent transcription. For example, whereas the E2A portion of the E2A-Pbx1 leukemia fusion protein mediates robust transcriptional activation in t(1;19) acute lymphoblastic leukemia, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) acute myeloid leukemia and ETO-2 in hematopoietic cells. Here, we show that, unlike the HEB E-protein, the activation domain 1 (AD1) of E2A has specifically reduced corepressor interaction due to E2A-specific amino acid changes in the p300/CBP and ETO target motif. Replacing E2A-AD1 with HEB-AD1 abolished the ability of E2A-Pbx1 to activate target genes and to induce cell transformation. On the other hand, the weak E2A-AD1-corepressor interaction imposes a critical importance on another ETO-interacting domain, downstream ETO-interacting sequence (DES), for corepressor-mediated repression. Deletion of DES abrogates silencing of E2A activity by AML1-ETO in t(8;21) leukemia cells or by ETO-2 in normal hematopoietic cells. Our results reveal an E2A-specific mechanism important for its context-dependent activation and repression function, and provide the first evidence for the differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.

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Section: Resultsmentioning

confidence: 99%

Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways

Gow

Guo

Wang

et al. 2013

Nucleic Acids Research

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“…Mtg16 is a relatively weak interactor with E47 compared with Heb and it appears to be dispensable for the development of Lmo2-induced T-cell leukemia since it is absent in the 080 line (50). Even so, it is required for normal T-cell development and it is part of the Lmo2-associated complex in erythroid progenitor cells (51). We were unable to isolate 080 lines that co-expressed E47-ER and Mtg16 which may imply that these two cooperate to induce growth arrest.…”

Section: Discussionmentioning

confidence: 99%

Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias

et al. 2015

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LIM domain Only-2 (LMO2) overexpression in T cells induces leukemia but the molecular mechanism remains to be elucidated. In hematopoietic stem and progenitor cells, Lmo2 is part of a protein complex comprised of class II basic helix loop helix proteins, Tal1and Lyl1. The latter transcription factors heterodimerize with E2A proteins like E47 and Heb to bind E boxes. LMO2 and TAL1 or LYL1 cooperate to induce T-ALL in mouse models, and are concordantly expressed in human T-ALL. Furthermore, LMO2 cooperates with the loss of E2A suggesting that LMO2 functions by creating a deficiency of E2A. In this study, we tested this hypothesis in Lmo2-induced T-ALL cell lines. We transduced these lines with an E47/estrogen receptor fusion construct that could be forced to homodimerize with 4-hydroxytamoxifen. We discovered that forced homodimerization induced growth arrest in 2 of the 4 lines tested. The lines sensitive to E47 homodimerization accumulated in G1 and had reduced S phase entry. We analyzed the transcriptome of a resistant and a sensitive line to discern the E47 targets responsible for the cellular effects. Our results suggest that E47 has diverse effects in T-ALL but that functional deficiency of E47 is not a universal feature of Lmo2-induced T-ALL.

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“…Consistently, ETO-2-deficient long-term HSCs showed cell-cycle blockage at the S phase (Fischer et al, 2012). A recent work showed that loss of ETO-2 compromises T cell development (Hunt et al, 2011). While this finding is consistent with ETO-2 regulation of E-protein’s transcriptional activities, it seems incompatible with a corepressor function of ETO-2, given that E-proteins are positive regulators of T cell development.…”

Section: Eto/e-protein Axis In Leukemogenesis and Hematopoiesismentioning

confidence: 99%

“…While this finding is consistent with ETO-2 regulation of E-protein’s transcriptional activities, it seems incompatible with a corepressor function of ETO-2, given that E-proteins are positive regulators of T cell development. It is possible that the observed defects in T cell development reflect a defect of HSCs given the aforementioned role of ETO-2 in HSC regulation, along with the diminished Notch activity in ETO-2-deficient cells (Chyla et al, 2008; Hunt et al, 2011). …”

Section: Eto/e-protein Axis In Leukemogenesis and Hematopoiesismentioning

confidence: 99%

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

Guo

Steinauer

et al. 2016

Front. Biol.

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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.

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Mtg16/Eto2 Contributes to Murine T-Cell Development

Cited by 28 publications

References 49 publications

Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways

Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways

Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

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