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PMID: 15326310 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 36 ·2004-09-07 ·Pages 13312-7

Helbling D, Mueller BU, Timchenko NA, Hagemeijer A, Jotterand M, Meyer-Monard S, Lister A, Rowley JD, Huegli B, Fey MF, Pabst T

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.

MeSH Terms
Adult Aged CCAAT-Enhancer-Binding Protein-alpha/genetics,physiology Calreticulin/physiology Core Binding Factor Alpha 2 Subunit Female Humans Leukemia, Myeloid, Acute/genetics,therapy Male Middle Aged Oncogene Proteins, Fusion/genetics RNA, Small Interfering/pharmacology Repressor Proteins/genetics Translocation, Genetic U937 Cells
Chemicals
AML1-MDS1-EVI1 fusion protein, human CCAAT-Enhancer-Binding Protein-alpha Calreticulin Core Binding Factor Alpha 2 Subunit Oncogene Proteins, Fusion RNA, Small Interfering Repressor Proteins
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Helbling Daniel
Institute of Medical Oncology, University Hospital, CH-3010 Bern, Switzerland.
Mueller Beatrice U
Timchenko Nikolai A
Hagemeijer Anne
Jotterand Martine
Meyer-Monard Sandrine
Lister Andrew
Rowley Janet D
Huegli Barbara
Fey Martin F
Pabst Thomas
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0404731101
Published
2004-09-07
Epub
2004-00-23
Pages
13312-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC516564
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0404731101 PMC Full Text View journal details
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