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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. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-03-1283v1 106/10/3559    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Thomas, M. Articles by Heidenreich, O. Search for Related Content PubMed PubMed Citation Articles by Thomas, M. Articles by Heidenreich, O. Related Collections Neoplasia Oncogenes and Tumor Suppressors Gene Expression Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Leukemia RNAi: harnessing the killer within Nancy J. Zeleznik-Le Blood 2005 106: 3336-3337. [Full Text] [PDF] This article has been cited by other articles: H. Nakanishi, T. Nakamura, E. Canaani, and C. M. Croce ALL1 fusion proteins induce deregulation of EphA7 and ERK phosphorylation in human acute leukemias PNAS, September 4, 2007; 104(36): 14442 - 14447. [Abstract] [Full Text] [PDF] C. Diakos, G. Krapf, C. Gerner, A. Inthal, C. Lemberger, J. Ban, A. M. Dohnal, and E. R. Panzer-Gruemayer RNAi-mediated silencing of TEL/AML1 reveals a heat-shock protein- and survivin-dependent mechanism for survival Blood, March 15, 2007; 109(6): 2607 - 2610. [Abstract] [Full Text] [PDF]

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