Interaction of AF4 wild-type and AF4.MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology?
The human AF4 (ALL-1 fused gene on chromosome 4) gene (4q11) is recurrently involved in reciprocal translocations to the MLL (mixed lineage leukemia) gene (11q23), correlated with high-risk acute lymphoblastic leukemia (ALL) in infants and early childhood. The t(4;11) translocation is one of the most frequent MLL translocations known today. In general, MLL translocations are the result of an illegitimate recombination process leading to reciprocal fusions of unrelated translocation partner (TP) genes with the MLL gene. Owing to the constant presence of the derivative (11) product, it was hypothesised that only MLL.TP fusion genes are responsible for the leukemogenic process. This concept has been successfully tested for some known MLL fusions, while other MLL fusions failed. Here, we demonstrate growth-transforming potential of AF4 wild-type and the AF4.MLL fusion protein. The underlying oncogenic mechanism involves the two E3 ubiquitin ligases SIAH1 and SIAH2, the N-terminal portion of AF4 and the protection of the AF4.MLL fusion protein against proteosomal degradation.
Bursen
Adelheid
A
Institute of Pharmaceutical Biology, Biocenter N230, University of Frankfurt/Main, Marie-Curie-Str. 9, Frankfurt/Main D-60439, Germany.
Moritz
Sven
S
Gaussmann
Anne
A
Moritz
Sören
S
Dingermann
Theo
T
Marschalek
Rolf
R
D000818:Animals; D002455:Cell Division; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D014178:Translocation, Genetic; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
C489900:Aff1 protein, mouse; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins