MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function.
MLL-AFX is a fusion gene created by t(X;11) chromosomal translocations in a subset of acute leukemias of either myeloid or lymphoid derivation. It codes for a chimeric protein consisting of MLL fused to AFX, a forkhead transcription factor that normally regulates genes involved in apoptosis and cell cycle progression. We demonstrate here that forced expression of MLL-AFX enhances the self-renewal of hematopoietic progenitors in vitro and induces acute myeloid leukemias after long latencies in syngeneic recipient mice. MLL-AFX interacts with the transcriptional coactivator CBP, which is also a fusion partner for MLL in human leukemias. A potent minimal transactivation domain (CR3) at the C terminus of AFX mediates interactions with the KIX domain of CBP and is necessary for transformation of myeloid progenitors by MLL-AFX. However, CR3 alone is not sufficient, suggesting that simple acquisition of a transactivation domain per se does not activate the oncogenic potential of MLL. Rather, two conserved transcriptional effector domains (CR2 and CR3) of AFX are required for full oncogenicity of MLL-AFX and also endow it with the potential to competitively interfere with transcription and apoptosis mediated by wild-type forkhead proteins. Furthermore, a dominant-negative mutant of AFX containing CR2 and CR3 enhances the growth of myeloid progenitors in vitro, although considerably less effectively than does MLL-AFX. Taken together, these data suggest that recruitment of transcriptional cofactors utilized by forkhead proteins is a critical requirement for oncogenic action of MLL-AFX, which may impact both MLL- and forkhead-dependent transcriptional pathways.
Department of Pathology, Stanford University School of Medicine, California 94305, USA.
Chi Wai
CW
So
Michael L
ML
Cleary
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D018797:Cell Cycle Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D051858:Forkhead Transcription Factors; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000502:physiology*; D010641:Phenotype; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; C497422:KMT2A protein, human; C465587:MLL-AFX protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D004247:DNA; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D005982:Glutathione Transferase