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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1369-1375.
Prepublished online as a Blood First Edition Paper on April 26, 2005; DOI 10.1182/blood-2004-11-4392.
 Previous Article | Next Article 
Submitted November 17, 2004
Accepted April 14, 2005
CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16)
Daniel Helbling, Beatrice U Mueller, Nikolai A Timchenko, Julian Schardt, Myriam Eyer, David R Betts, Martine Jotterand, Sandrine Meyer-Monard, Martin F Fey, and Thomas Pabst*
Department of Clinical Research and Department of Medical Oncology, University Hospital, Berne, Switzerland
Department of Medicine, University Hospital, Berne, Switzerland
Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA
Department of Oncology, University Children Hospital, Zurich, Switzerland
Unit of Cancer Cytogenetics; Service of Medical Genetics, University Hospital, Lausanne, Switzerland
Division of Haematology, University Hospital, Basel, Switzerland
* Corresponding author; email: thomas.pabst{at}insel.ch.
The pericentric inversion of chromosome 16, inv(16)(p13q22), is associated with AML subtype M4Eo that is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This rearrangement fuses the CBF and MYH11 genes, with the latter encoding the smooth muscle myosin heavy chain (SMMHC). The myeloid transcription factor CEBPA is crucial for normal granulopoiesis. Alterations of structure and expression of CEBPA have been implicated in particular subtypes of AML. Here, we found that conditional expression of CBF-SMMHC in U937 cells suppresses CEBPA protein expression and binding activity. However, CEBPA mRNA levels remained unchanged. No differences were detected in CEBPA mRNA levels in patients with inv(16) AML-M4Eo (n=12) compared to AML patients with a normal karyotype and M4 subtype (n=6), whereas CEBPA protein and binding activity were significantly reduced in patients with CBF-SMMHC. Furthermore, Calreticulin, an inhibitor of CEBPA translation, was induced on mRNA and protein level in CBF-SMMHC AML patients and after expression of CBF-SMMHC in the U937 cell system. Inhibition of Calreticulin by siRNA restored CEBPA levels. Our results suggest that modulation of CEBPA by Calreticulin represents a novel mechanism involved in the differentiation block in CBF-SMMHC AML.
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