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

4 Citations (Scopus)

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

Fingerprint

Estradiol
Genes
Introns
Reverse Transcription
Polymerase Chain Reaction
DNA Cleavage
Gene Rearrangement
Chromatin Immunoprecipitation
RNA Interference
Contraception
AICDA (activation-induced cytidine deaminase)
Leukemia
Chromosomes
Pregnancy

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Estradiol induces gene proximity and MLL-MLLT3 fusion in an activation-induced cytidine deaminase-mediated pathway. / Wright, Rebecca L.; Slemmons, Katherine K.; Vaughan, Andrew T M.

In: Leukemia and Lymphoma, Vol. 56, No. 5, 01.05.2015, p. 1460-1465.

Research output: Contribution to journalArticle

@article{5e7b399053c2443b826fdc2537ac9797,
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.",
keywords = "3C, AICDA, Estradiol, IAL, MLL, MLLT3",
author = "Wright, {Rebecca L.} and Slemmons, {Katherine K.} and Vaughan, {Andrew T M}",
year = "2015",
month = "5",
day = "1",
doi = "10.3109/10428194.2014.954112",
language = "English (US)",
volume = "56",
pages = "1460--1465",
journal = "Leukemia and Lymphoma",
issn = "1042-8194",
publisher = "Informa Healthcare",
number = "5",

}

TY - JOUR

T1 - Estradiol induces gene proximity and MLL-MLLT3 fusion in an activation-induced cytidine deaminase-mediated pathway

AU - Wright, Rebecca L.

AU - Slemmons, Katherine K.

AU - Vaughan, Andrew T M

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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.

AB - 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.

KW - 3C

KW - AICDA

KW - Estradiol

KW - IAL

KW - MLL

KW - MLLT3

UR - http://www.scopus.com/inward/record.url?scp=84932098842&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84932098842&partnerID=8YFLogxK

U2 - 10.3109/10428194.2014.954112

DO - 10.3109/10428194.2014.954112

M3 - Article

C2 - 25130479

AN - SCOPUS:84932098842

VL - 56

SP - 1460

EP - 1465

JO - Leukemia and Lymphoma

JF - Leukemia and Lymphoma

SN - 1042-8194

IS - 5

ER -