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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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NEOPLASIA

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

From the 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; and Alnylam Europe AG, Kulmbach, Germany.

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 mixed-lineage leukemia (MLL)–ALL-1 fused gene from chromosome 4 (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 expression of the stem-cell marker CD133, indicating hematopoietic differentiation. Transfection of leukemic cells with MLL-AF4 siRNAs reduces leukemia-associated morbidity and mortality in SCID mice that received a xenotransplant, 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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