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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3559-3566.
Prepublished online as a Blood First Edition Paper on July 26, 2005; DOI 10.1182/blood-2005-03-1283.
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Submitted March 30, 2005
Accepted July 10, 2005
Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells
Maria Thomas, Andreas Gessner, Hans-Peter Vornlocher, Philipp Hadwiger, Johann Greil, and Olaf Heidenreich*
Department of Molecular Biology, Interfaculty Institute for Cell Biology, Eberhard Karls University of Tuebingen, Tuebingen, Germany; Department of Pediatric Hematology and Oncology, University Children's Hospital, Tuebingen, Germany
Department of Molecular Biology, Interfaculty Institute for Cell Biology, Eberhard Karls University of Tuebingen, Tuebingen, Germany
Alnylam Europe AG, Kulmbach, Germany
Department of Pediatric Hematology and Oncology, University Children's Hospital, Tuebingen, Germany
* Corresponding author; email: olaf.heidenreich{at}uni-tuebingen.de.
The chromosomal translocation t(4;11) marks infant acute lymphoblastic leukemia associated with a particularly dismal prognosis. The leukemogenic role of the corresponding fusion gene MLL-AF4 is not well understood. We show that transient inhibition of MLL-AF4 expression with small interfering RNAs impairs the proliferation and clonogenicity of the t(4;11)-positive human leukemic cell lines SEM and RS4;11. Reduction of MLL-AF4 levels induces apoptosis associated with caspase-3 activation and diminished BCL-XL expression. Suppression of MLL-AF4 is paralleled by a decreased expression of the homeotic genes HOXA7, HOXA9 and MEIS1. MLL-AF4 depletion inhibits the expression of the stem cell marker CD133 indicating hemopoietic differentiation. Transfection of leukemic cells with MLL-AF4 siRNAs reduces leukemia-associated morbidity and mortality in xenotransplanted SCID mice suggesting that MLL-AF4 depletion negatively affects leukemia-initiating cells. Our findings demonstrate that MLL-AF4 is important for leukemic clonogenicity and engraftment of this highly aggressive leukemia. Targeted inhibition of MLL-AF4 fusion gene expression may lead to an effective and highly specific treatment of this therapy-resistant leukemia.
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