The mixed lineage leukemia fusion partner AF9 binds specific isoforms of the BCL-6 corepressor

• Published in: Oncogene Vol. 22; no. 22; pp. 3395 - 3406
• Main Authors: SATHISH SRINIVASAN, R, DE ERKENEZ, Andrea C, HEMENWAY, Charles S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 29.05.2003; Nature Publishing Group
• Subjects: Acute myeloid leukemia; Alternative Splicing; Amino Acid Sequence; Animals; Bcl-6 protein; Biological and medical sciences; Chromosome 11; Chromosome translocations; Chromosomes; Cloning; DNA-Binding Proteins; Fundamental and applied biological sciences. Psychology; Fusion protein; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Insects; Isoforms; Leukemia; Leukemia - genetics; Leukemogenesis; Mice; Molecular and cellular biology; Molecular Sequence Data; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pediatrics; Protein Isoforms; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-6; Reporter gene; Repressor Proteins - genetics; Repressor Proteins - isolation & purification; Repressor Proteins - metabolism; RNA polymerase; SWI/SNF complex; Transcription; Transcription Factors; Transcription, Genetic; Two-Hybrid System Techniques; United States > US; gene repression; Genetics; oncogenic fusion proteins; leukemia cell lines; alternative RNA splicing
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206361

The mixed lineage leukemia (MLL) gene at chromosome band 11q23 is commonly involved in reciprocal translocations that are detected in acute leukemias. Evidence suggests that the resulting MLL fusion genes contribute to leukemogenesis. AF9 is a common MLL fusion partner in acute myeloid leukemia. The AF9 protein functions as a transcriptional activator in artificial reporter gene assays and a structurally related protein in yeast, ANC1/TFG3, is a component of the SWI/SNF complex. Apart from these observations, little is known about the biologic function of AF9 in mammals. We have found that a recently described transcriptional repressor, BCL-6 corepressor (BCoR), interacts with the carboxy-terminus of AF9. The interaction of AF9 with BCoR has been confirmed by independent in vitro and in vivo protein-binding studies. The BCoR gene is expressed as several alternatively spliced transcripts. AF9 only binds BCoR isoforms that contain a unique 34 aa sequence located in the mid-portion of the protein. In artificial reporter gene assays, a BCoR isoform that binds AF9 efficiently suppresses AF9 transcriptional activity, while a nonbinding isoform does not. These results indicate that different isoforms of BCoR have unique biologic properties and that cell function may be partly determined by the different isoforms that are present within the cell.