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Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells

Lookup NU author(s): Professor Olaf Heidenreich

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Abstract

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-X(L) 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.


Publication metadata

Author(s): Thomas M, Gessner A, Vornlocher HP, Hadwiger P, Greil J, Heidenreich O

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2005

Volume: 106

Issue: 10

Pages: 3559-3566

Print publication date: 26/07/2005

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

URL: http://dx.doi.org/10.1182/blood-2005-03-1283

DOI: 10.1182/blood-2005-03-1283


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