Journal
LEUKEMIA
Volume 25, Issue 4, Pages 663-670Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2010.308
Keywords
acute leukemia; MLL; AF4; fusion genes; fusion proteins
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Funding
- Deutsche Krebshilfe e.V. [102363]
- Boehringer Ingelheim
- Wilhelm-Sander Foundation
- Chemical Industry
- Chemical Industry, and the Stiftung Rheinland-Pfalz fur Innovationen
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The chromosomal translocation t(4;11)(q21;q23) is a frequent genetic aberration of the mixed lineage leukemia (MLL) gene, predominantly associated with high-risk acute lymphoblastic leukemia (ALL) in pediatric patients. Previous studies demonstrated that mice transplanted with hematopoietic cells expressing the AF4-MLL fusion protein develop proB ALL. The AF4-MLL oncoprotein becomes activated by Taspase1-mediated hydrolysis, which subsequently leads to a heterodimer of the cleavage products AF4-MLL . N and MLL . C. This protein-protein interaction is due to the FYRN and FYRC interaction domains present in both protein fragments. Heterodimerization subsequently induces high-molecular-weight protein complex formation that is protected against SIAH1/2-mediated polyubiquitinylation. Here, we attempted to selectively block this initial heterodimerization step, aiming to prevent the oncogenic activation of the AF4-MLL multiprotein complex. The minimal interaction interface was experimentally defined first in a bacterial two-hybrid system, and then in mammalian cells by using a biosensor assay. Expression of the FYRC domain, or smaller portions thereof, resulted in the inhibition of heterodimer formation, and blocked AF4-MLL multiprotein complex formation with subsequent destruction of the AF4-MLL oncoprotein. Thus, it is in principle possible to specifically target the AF4-MLL protein. This knowledge can now be exploited to design inhibitory decoys in order to destroy the AF4-MLL oncoprotein. Leukemia (2011) 25, 663-670; doi:10.1038/leu.2010.308; published online 14 January 2011
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