title: Estradiol induces gene proximity and MLL-MLLT3 fusion in an activation-induced cytidine deaminase-mediated pathway.
abstract: Epidemiological data have linked birth control formulations to an increased risk of infant acute leukemia involving MLL rearrangements. Reverse transcription polymerase chain reaction (RT-PCR) studies showed that 10 nM estradiol enhanced MLL transcription in addition to its common translocation partners, MLLT2 (AF4) and MLLT3 (AF9). The same concentration of estradiol triggered MLL and MLLT3 co-localization without affecting the interaction of genes located on the same chromosomes. Estradiol also stimulated the generation of MLL-MLLT3 fusion transcripts as seen by RT-PCR. RNAi knockdown of activation-induced cytidine deaminase (AICDA) suppressed the induction of MLL-MLLT3 fusion transcript formation observed with estradiol. Additionally, chromatin immunoprecipitation (ChIP) analysis showed estradiol dependent localization of AICDA in MLL intron 11, upstream of a hotspot for both DNA cleavage and rearrangement, but not downstream within intron 12. Combined, these studies show that levels of estradiol consistent with that observed during pregnancy have the potential to initiate MLL fusions through an AICDA-mediated mechanism.
authors.affiliation: Department of Radiation Oncology, University of California at Davis , Sacramento, CA , USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Wright
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Slemmons
authors.forename: Andrew T M
authors.initials: AT
authors.lastname: Vaughan
mesh_terms: D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056426:Genetic Loci; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C529663:MLL-MLLT3 fusion protein, human; C489901:MLLT3 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D004958:Estradiol; D011495:Histone-Lysine N-Methyltransferase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: 3C; AICDA; IAL; MLL; MLLT3; estradiol