PMID- 28663574
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20181211
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 32
IP  - 1
DP  - 2018 Jan
TI  - Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia.
PG  - 11-20
LID - 10.1038/leu.2017.171 [doi]
AB  - The genomes of myeloid malignancies are characterized by epigenomic
      abnormalities. Heterozygous, inactivating ten-eleven translocation 2 (TET2)
      mutations and neomorphic isocitrate dehydrogenase (IDH) mutations are recurrent
      and mutually exclusive in acute myeloid leukaemia genomes. Ascorbic acid (vitamin
      C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus
      we sought to explore its effect in a leukaemic model expressing IDH1(R132H).
      Vitamin C treatment induced an IDH1(R132H)-dependent reduction in cell
      proliferation and an increase in expression of genes involved in leukocyte
      differentiation. Vitamin C induced differentially methylated regions that
      displayed a significant overlap with enhancers implicated in myeloid
      differentiation and were enriched in sequence elements for the haematopoietic
      transcription factors CEBPbeta, HIF1alpha, RUNX1 and PU.1. Chromatin
      immunoprecipitation sequencing of PU.1 and RUNX1 revealed a significant loss of
      PU.1 and increase of RUNX1-bound DNA elements accompanied by their demethylation 
      following vitamin C treatment. In addition, vitamin C induced an increase in
      H3K27ac flanking sites bound by RUNX1. On the basis of these data we propose a
      model of vitamin C-induced epigenetic remodelling of transcription factor-binding
      sites driving differentiation in a leukaemic model.
FAU - Mingay, M
AU  - Mingay M
AD  - Department of Microbiology and Immunology, Michael Smith Laboratories Centre for 
      High-Throughput Biology, University of British Columbia, Vancouver, British
      Columbia, Canada.
FAU - Chaturvedi, A
AU  - Chaturvedi A
AD  - Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,
      Hannover Medical School, Hannover, Germany.
FAU - Bilenky, M
AU  - Bilenky M
AD  - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver,
      British Columbia, Canada.
FAU - Cao, Q
AU  - Cao Q
AD  - Department of Microbiology and Immunology, Michael Smith Laboratories Centre for 
      High-Throughput Biology, University of British Columbia, Vancouver, British
      Columbia, Canada.
FAU - Jackson, L
AU  - Jackson L
AD  - Department of Microbiology and Immunology, Michael Smith Laboratories Centre for 
      High-Throughput Biology, University of British Columbia, Vancouver, British
      Columbia, Canada.
FAU - Hui, T
AU  - Hui T
AD  - Department of Microbiology and Immunology, Michael Smith Laboratories Centre for 
      High-Throughput Biology, University of British Columbia, Vancouver, British
      Columbia, Canada.
FAU - Moksa, M
AU  - Moksa M
AD  - Department of Microbiology and Immunology, Michael Smith Laboratories Centre for 
      High-Throughput Biology, University of British Columbia, Vancouver, British
      Columbia, Canada.
FAU - Heravi-Moussavi, A
AU  - Heravi-Moussavi A
AD  - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver,
      British Columbia, Canada.
FAU - Humphries, R K
AU  - Humphries RK
AD  - Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
FAU - Heuser, M
AU  - Heuser M
AD  - Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,
      Hannover Medical School, Hannover, Germany.
FAU - Hirst, M
AU  - Hirst M
AUID- ORCID: 0000-0001-9136-9054
AD  - Department of Microbiology and Immunology, Michael Smith Laboratories Centre for 
      High-Throughput Biology, University of British Columbia, Vancouver, British
      Columbia, Canada.
AD  - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver,
      British Columbia, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170602
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - EC 1.1.1.42 (Idh1 protein, mouse)
RN  - PQ6CK8PD0R (Ascorbic Acid)
SB  - IM
MH  - Animals
MH  - Ascorbic Acid/*pharmacology
MH  - Cell Differentiation/drug effects
MH  - Cell Proliferation/drug effects
MH  - DNA-Binding Proteins/genetics
MH  - Epigenesis, Genetic/*drug effects
MH  - Epigenomics/methods
MH  - Isocitrate Dehydrogenase/*genetics
MH  - Leukemia, Myeloid, Acute/*genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mutation/*genetics
MH  - Transcription Factors/genetics
PMC - PMC5770587
EDAT- 2017/07/01 06:00
MHDA- 2018/12/12 06:00
CRDT- 2017/07/01 06:00
PHST- 2016/10/11 00:00 [received]
PHST- 2017/04/19 00:00 [revised]
PHST- 2017/05/16 00:00 [accepted]
PHST- 2017/07/01 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2017/07/01 06:00 [entrez]
AID - leu2017171 [pii]
AID - 10.1038/leu.2017.171 [doi]
PST - ppublish
SO  - Leukemia. 2018 Jan;32(1):11-20. doi: 10.1038/leu.2017.171. Epub 2017 Jun 2.