The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin

Details

Serval ID
serval:BIB_437F396477ED
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Helbling  D., Mueller  B. U., Timchenko  N. A., Hagemeijer  A., Jotterand  M., Meyer-Monard  S., Lister  A., Rowley  J. D., Huegli  B., Fey  M. F., Pabst  T.
ISSN
0027-8424 (Print)
Publication state
Published
Issued date
09/2004
Volume
101
Number
36
Pages
13312-7
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Sep 7
Abstract
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.
Keywords
Adult Aged CCAAT-Enhancer-Binding Protein-alpha/genetics/*physiology Calreticulin/*physiology Core Binding Factor Alpha 2 Subunit Female Humans Leukemia, Myelocytic, Acute/*genetics/therapy Male Middle Aged Oncogene Proteins, Fusion/*genetics RNA, Small Interfering/pharmacology Repressor Proteins/*genetics Translocation, Genetic U937 Cells
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 14:18
Last modification date
20/08/2019 13:47
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