Estradiol induces gene proximity andMLL–MLLT3fusion 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.

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

“…In a recent study addressing the role of prenatal hormone exposure in MLL translocations leading to infant ALL, estradiol-induced MLL and MLLT3/AF9 colocalization as well as fusion transcript formation were detected. Interestingly, this process required the protein activation-induced cytidine deaminase, AID (Wright et al, 2014 ). Even though primarily known to be involved in targeted Ig gene maturation processes, AID has also been shown to exert unspecific genotoxic effects upon activation by estrogen (Pauklin et al, 2009 ).…”

“…Even though primarily known to be involved in targeted Ig gene maturation processes, AID has also been shown to exert unspecific genotoxic effects upon activation by estrogen (Pauklin et al, 2009 ). ChIP experiments revealed localization of AID in MLLbcr intron 11 (Wright et al, 2014 ), to where it may become recruited by stalled RNA polymerase in analogy to the situation during Ig gene switching (Pavri et al, 2010 ). Given that aberrantly activated AID can cleave at 150 target sites outside of Ig genes including well-described translocation hotspots (Hakim et al, 2012 ), it represents a key candidate for involvement in genome rearrangements following transcription stalling.…”

Mutagenic Consequences of Sublethal Cell Death Signaling

“…Interestingly, components for base excision repair (BER) were localized to regions of EndoG-mediated MLL cleavage after treatment with the DNA polymerase inhibitor aphidicolin, rather than NHEJ proteins [ 204 ]. This may be because EndoG can process both single- and double-stranded DNA or probably reflects the contribution from other MLL cleavage-causing factors upon replication stress, such as activation-induced cytidine deaminase during transcription, which can also localize to MLL- bcr active areas [ 204 , 205 ]. Furthermore, BER commonly repairs oxidative stress-induced DNA damage [ 206 ], and oxidative stress as a result of reactive oxygen species (ROS) can promote mitochondrial damage [ 207 ].…”