Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ohlsson, Ewa, Hasemann, Marie Sigurd, Willer, Anton, Lauridsen, Felicia Kathrine Bratt, Rapin, Nicolas, Jendholm, Johan, Porse, Bo Torben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
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
_version_ 1782299616310460416
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
work_keys_str_mv AT ohlssonewa initiationofmllrearrangedamlisdependentoncebpa
AT hasemannmariesigurd initiationofmllrearrangedamlisdependentoncebpa
AT willeranton initiationofmllrearrangedamlisdependentoncebpa
AT lauridsenfeliciakathrinebratt initiationofmllrearrangedamlisdependentoncebpa
AT rapinnicolas initiationofmllrearrangedamlisdependentoncebpa
AT jendholmjohan initiationofmllrearrangedamlisdependentoncebpa
AT porsebotorben initiationofmllrearrangedamlisdependentoncebpa