Estradiol induces gene proximity and MLL-MLLT3 fusion in an activation-induced cytidine deaminase-mediated pathway

Rebecca L. Wright, Katherine K. Slemmons, Andrew T M Vaughan

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1460-1465
Number of pages6
JournalLeukemia and Lymphoma
Volume56
Issue number5
DOIs
StatePublished - May 1 2015

Keywords

  • 3C
  • AICDA
  • Estradiol
  • IAL
  • MLL
  • MLLT3

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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