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Initiation of MLL-rearranged AML is dependent on C/EBPα
MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional pr...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892979/ https://www.ncbi.nlm.nih.gov/pubmed/24367003 http://dx.doi.org/10.1084/jem.20130932 |
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author | Ohlsson, Ewa Hasemann, Marie Sigurd Willer, Anton Lauridsen, Felicia Kathrine Bratt Rapin, Nicolas Jendholm, Johan Porse, Bo Torben |
author_facet | Ohlsson, Ewa Hasemann, Marie Sigurd Willer, Anton Lauridsen, Felicia Kathrine Bratt Rapin, Nicolas Jendholm, Johan Porse, Bo Torben |
author_sort | Ohlsson, Ewa |
collection | PubMed |
description | MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL–induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion–driven transformation and find that it sharply demarcates tumor initiation and maintenance. |
format | Online Article Text |
id | pubmed-3892979 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-38929792014-07-13 Initiation of MLL-rearranged AML is dependent on C/EBPα Ohlsson, Ewa Hasemann, Marie Sigurd Willer, Anton Lauridsen, Felicia Kathrine Bratt Rapin, Nicolas Jendholm, Johan Porse, Bo Torben J Exp Med Brief Definitive Report MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL–induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion–driven transformation and find that it sharply demarcates tumor initiation and maintenance. The Rockefeller University Press 2014-01-13 /pmc/articles/PMC3892979/ /pubmed/24367003 http://dx.doi.org/10.1084/jem.20130932 Text en © 2014 Ohlsson et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Brief Definitive Report Ohlsson, Ewa Hasemann, Marie Sigurd Willer, Anton Lauridsen, Felicia Kathrine Bratt Rapin, Nicolas Jendholm, Johan Porse, Bo Torben Initiation of MLL-rearranged AML is dependent on C/EBPα |
title | Initiation of MLL-rearranged AML is dependent on C/EBPα |
title_full | Initiation of MLL-rearranged AML is dependent on C/EBPα |
title_fullStr | Initiation of MLL-rearranged AML is dependent on C/EBPα |
title_full_unstemmed | Initiation of MLL-rearranged AML is dependent on C/EBPα |
title_short | Initiation of MLL-rearranged AML is dependent on C/EBPα |
title_sort | initiation of mll-rearranged aml is dependent on c/ebpα |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892979/ https://www.ncbi.nlm.nih.gov/pubmed/24367003 http://dx.doi.org/10.1084/jem.20130932 |
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