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AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells

Lookup NU author(s): Professor Olaf Heidenreich

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Abstract

The translocation t(8;21) yields the leukemic fusion gene AML1/MTG8 and is associated with 10%-15% of all de novo cases of acute myeloid leukemia. We demonstrate the efficient and specific suppression of AML1/MTG8 by small interfering RNAs (siRNAs) in the human leukemic cell lines Kasumi-1 and SKNO-1. siRNAs targeted against the fusion site of the AML1/MTG8 mRNA reduce the levels of AML1/MTG8 without affecting the amount of wild-type AML1. These data argue against a transitive RNA interference mechanism potentially induced by siRNAs in such leukemic cells. Depletion of AML1/MTG8 correlates with an increased susceptibility of both Kasumi-1 and SKNO-1 cells to tumor growth factor beta(1) (TGFbeta(1))/vitamin D(3)-induced differentiation, leading to increased expression of CD11b, macrophage colony-stimulating factor (M-CSF) receptor, and C/EBPalpha (CAAT/enhancer binding protein). Moreover, siRNA-mediated AML1/MTG8 suppression results in changes in cell shape and, in combination with TGFbeta(1)/vitamin D(3), severely reduces clonogenicity of Kasumi-1 cells. These results suggest an important role for AML1/MTG8 in preventing differentiation, thereby propagating leukemic blast cells. Therefore, siRNAs are promising tools for a functional analysis of AML1/MTG8 and may be used in a molecularly defined therapeutic approach for t(8;21)-positive leukemia.


Publication metadata

Author(s): Heidenreich O, Krauter J, Riehle H, Hadwiger P, John M, Heil G, Vornlocher HP, Nordheim A

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2003

Volume: 101

Issue: 8

Pages: 3157-3163

Print publication date: 12/12/2002

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

URL: http://dx.doi.org/10.1182/blood-2002-05-1589

DOI: 10.1182/blood-2002-05-1589


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