1. ¹Cancer Research UK Medical Oncology Laboratory, Barts and the London School of Medicine, London, UK
2. ²Department of Molecular Biology, Interfaculty Institute of Cell Biology, Faculty of Biology, Eberhard Karls University Tuebingen, Germany
3. ³Department of Haematology, Oncology and Immunology, University Hospital Marburg, Germany
4. ⁴Department of Haematology, Haemostaseology and Oncology, Hannover Medical School, Hannover, Germany
5. ⁵Institute for Medical Biometry and Epidemiology, Philipps University Marburg, Germany
6. ⁶Institute for Molecular Biology and Tumour Research, Philipps University Marburg, Germany

Correspondence: Dr O Heidenreich, Department of Molecular Biology, Interfaculty Institute of Cell Biology, Faculty of Biology, Eberhard Karls University Tuebingen, Auf der Morgenstelle 15, 72076 Tuebingen, Germany. E-mail: olaf.heidenreich@uni-tuebingen.de

⁷These authors equally contributed to the work.

⁸Current address: Research Group Molecular Therapy of Virus-Associated Cancers, German Cancer Research Center, Heidelberg, Germany.

Received 22 December 2005; Revised 15 March 2006; Accepted 23 March 2006; Published online 1 May 2006.

Abstract

The chromosomal translocation t(8;21) is associated with 10–15% of all cases of acute myeloid leukaemia (AML). The resultant fusion protein AML1/MTG8 interferes with haematopoietic gene expression and is an important regulator of leukaemogenesis. We studied the effects of small interfering RNA (siRNA)-mediated AML1/MTG8 depletion on global gene expression in t(8;21)-positive leukaemic cell lines and in primary AML blasts using cDNA arrays, oligonucleotide arrays and real-time reverse transcription–polymerase chain reaction (RT–PCR). Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines. Furthermore, expression levels of several genes affiliated with drug resistance or indicative of poor prognosis AML (BAALC, CD34, PRG2, TSPAN7) are affected by AML1/MTG8 depletion. In conclusion, siRNA-mediated suppression of AML1/MTG8 cause very similar changes in gene expression pattern in t(8;21)-positive cell lines and in primary AML blasts. Furthermore, the results suggest that the specific targeting of AML1/MTG8 function may be a promising approach for complementing existing treatment strategies.