title: The heterodimerization domains of MLL-FYRN and FYRC--are potential target structures in t(4;11) leukemia.
abstract: 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.
authors.affiliation: Institute of Pharmaceutical Biology/ZAFES, Goethe-University of Frankfurt, Biocenter, Frankfurt/Main, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Pless
authors.forename: C
authors.initials: C
authors.lastname: Oehm
authors.forename: S
authors.initials: S
authors.lastname: Knauer
authors.forename: R H
authors.initials: RH
authors.lastname: Stauber
authors.forename: T
authors.initials: T
authors.lastname: Dingermann
authors.forename: R
authors.initials: R
authors.lastname: Marschalek
mesh_terms: D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015151:Immunoblotting; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D035602:Transcriptional Elongation Factors; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase