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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3535-3543.
Prepublished online as a Blood First Edition Paper on January 22, 2004; DOI 10.1182/blood-2003-09-3335.
Submitted September 29, 2003
Accepted January 1, 2004
 -catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells
Xiaomin Zheng, Tim Beissert, Natasa Kukoc-Zivojnov, Elena Puccetti, Joachim Altschmied, Corinna Strolz, Simone Boehrer, Hilal Gul, Orinta Schneider, Oliver G Ottmann, Dieter Hoelzer, Reinhard Henschler, and Martin Ruthardt*
Med. Klinik III/Experimentelle Haematologie, Klinikum der J.W. Goethe Universitaet, Frankfurt, Germany
Med. Klinik III/Molekulare Haematologie, Klinikum der J.W. Goethe Universitaet, Frankfurt, Germany
Institut fuer Transfusionsmedizin, Deutsches Rotes Kreuz, Frankfurt, Germany
* Corresponding author; email: ruthardt{at}em.uni-frankfurt.de.
Acute myeloid leukemia (AML) is characterized by the block of differentiation, deregulated apoptosis and an increased self-renewal of hematopoietic precursors. It is unclear whether the self-renewal of leukemic blasts results from the cumulative effects of blocked differentiation and impaired apoptosis or whether there are mechanisms directly increasing self-renewal. The AML-associated translocation products (AATP) PML/RAR , PLZF/RAR (X-RAR) and AML-1/ETO block hematopoietic differentiation. The AATPs activates the Wnt-signaling by up-regulating  -catenin. Activation of the Wnt-signaling augments self-renewal of hematopoietic stem cells (HSCs). Therefore we investigated how AATPs influence self-renewal of HSCs and evaluated the role of -catenin in the determination of the phenotype of HSCs expressing AATPs. Here we show, that the AATPs directly activate the -catenin promoter. The crucial role of -catenin in increasing the self-renewal of HSCs upon expression of AATPs is demonstrated by i.) the abrogation of replating efficiency upon hinderance of -catenin expression through RNA-interference; ii.) the augmentation of replating efficiency of HSCs upon over-expression of -catenin itself. In addition, the inoculation of -catenin transduced HSCs into irradiated recipient mice establishes the clinical picture of AML. These data provide first evidence that the aberrant activation of Wnt-signaling by the AATP decisively contributes to the pathogenesis of AML.
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