Journal article
GATA2 regulates the erythropoietin receptor in t(12;21) ALL
Oncotarget, Vol.8(39), pp.66061-66074
09/12/2017
DOI: 10.18632/oncotarget.19792
PMID: 29029492
Abstract
The t(12;21) (p13;q22) chromosomal translocation resulting in the
ETV6/RUNX1
fusion gene is the most frequent structural cytogenetic abnormality in children with acute lymphoblastic leukemia (ALL). The erythropoietin receptor (EPOR), usually associated with erythroid progenitor cells, is highly expressed in
ETV6/RUNX1
positive cases compared to other B-lineage ALL subtypes. Gene expression analysis of a microarray database and direct quantitative analysis of patient samples revealed strong correlation between
EPOR
and
GATA2
expression in ALL, and higher expression of
GATA2
in t(12;21) patients. The mechanism of EPOR regulation was mainly investigated using two B-ALL cell lines: REH, which harbor and express the
ETV6/RUNX1
fusion gene; and NALM-6, which do not. Expression of EPOR was increased in REH cells compared to NALM-6 cells. Moreover, of the six GATA family members only
GATA2
was differentially expressed with substantially higher levels present in REH cells.
GATA2
was shown to bind to the EPOR 5'-UTR in REH, but did not bind in NALM-6 cells. Overexpression of
GATA2
led to an increase in EPOR expression in REH cells only, indicating that GATA2 regulates EPOR but is dependent on the cellular context. Both
EPOR
and
GATA2
are hypomethylated and associated with increased mRNA expression in REH compared to NALM-6 cells. Decitabine treatment effectively reduced methylation of CpG sites in the
GATA2
promoter leading to increased
GATA2
expression in both cell lines. Although Decitabine also reduced an already low level of methylation of the EPOR in NALM-6 cells there was no increase in EPOR expression. Furthermore,
EPOR
and
GATA2
are regulated post-transcriptionally by miR-362 and miR-650, respectively. Overall our data show that EPOR expression in t(12;21) B-ALL cells, is regulated by GATA2 and is mediated through epigenetic, transcriptional and post-transcriptional mechanisms, contingent upon the genetic subtype of the disease.
Details
- Title: Subtitle
- GATA2 regulates the erythropoietin receptor in t(12;21) ALL
- Creators
- Marie E Gaine - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United KingdomDaniel J Sharpe - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United KingdomJames S Smith - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United KingdomHilary A.A Colyer - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United KingdomVivien M Hodges - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United KingdomTerry R Lappin - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United KingdomKen I Mills - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United Kingdom
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.8(39), pp.66061-66074
- Publisher
- Impact Journals LLC
- DOI
- 10.18632/oncotarget.19792
- PMID
- 29029492
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Language
- English
- Date published
- 09/12/2017
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984070494102771
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