Titre
The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Auteur(s)
Helbling, D.
Auteure/Auteur
Mueller, B. U.
Auteure/Auteur
Timchenko, N. A.
Auteure/Auteur
Hagemeijer, A.
Auteure/Auteur
Jotterand, M.
Auteure/Auteur
Meyer-Monard, S.
Auteure/Auteur
Lister, A.
Auteure/Auteur
Rowley, J. D.
Auteure/Auteur
Huegli, B.
Auteure/Auteur
Fey, M. F.
Auteure/Auteur
Pabst, T.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
0027-8424
Statut éditorial
Publié
Date de publication
2004-09
Volume
101
Numéro
36
Première page
13312
Dernière page/numéro d’article
7
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Sep 7
Research Support, Non-U.S. Gov't --- Old month value: Sep 7
Résumé
The leukemic fusion gene AML1-MDS1-EVI1 (AME) encodes a chimeric transcription factor that results from the t(3,21)(q26;q22) translocation seen in patients with acute myeloid leukemia, with therapy-related myelodysplastic syndrome, or with chronic myeloid leukemia in blast crisis. The myeloid transcription factor CEBPA is crucial for normal granulopoiesis. Here, we found that conditional expression of AME suppresses CEBPA protein by 90.8% and DNA-binding activity by 93.9%. In contrast, CEBPA mRNA levels remained unchanged. In addition, we detected no differences in CEBPA mRNA levels in leukemic blasts of patients carrying the AME translocation (n = 8) compared to acute myeloid leukemia patients with a normal karyotype (n = 9). CEBPA protein and binding activity, however, were reduced significantly (100% and 92.1%, respectively) in AME patient samples. Furthermore, we observed that calreticulin (CRT), a putative inhibitor of CEBPA translation, was strongly activated after induction of AME in the cell-line system (14.8-fold) and in AME patient samples (12.2-fold). Moreover, inhibition of CRT by small interfering RNA powerfully restored CEBPA levels. These results identify CEBPA as a key target of the leukemic fusion protein AME and suggest that modulation of CEBPA by CRT may represent a mechanism involved in the differentiation block in AME leukemias.
Sujets
PID Serval
serval:BIB_437F396477ED
PMID
Open Access
Oui
Date de création
2008-01-25T13:18:06.393Z
Date de création dans IRIS
2025-05-20T20:51:42Z