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@ARTICLE{Kiehlmeier:168557,
author = {S. Kiehlmeier$^*$ and M.-R. Rafiee and A. M. A. Bakr$^*$
and J. Mika$^*$ and S. Kruse$^*$ and J. Müller$^*$ and S.
Schweiggert$^*$ and C. Herrmann and G. Sigismondo$^*$ and P.
Schmezer$^*$ and J. Krijgsveld$^*$ and S. Gröschel$^*$},
title = {{I}dentification of therapeutic targets of the hijacked
super-enhancer complex in {EVI}1-rearranged leukemia.},
journal = {Leukemia},
volume = {35},
number = {11},
issn = {1476-5551},
address = {London},
publisher = {Springer Nature},
reportid = {DKFZ-2021-00974},
pages = {3127-3138},
year = {2021},
note = {#EA:A380#LA:A380# / 2021 Nov;35(11):3127-3138},
abstract = {Deregulation of the EVI1 proto-oncogene by the GATA2 distal
hematopoietic enhancer (G2DHE) is a key event in high-risk
acute myeloid leukemia carrying 3q21q26 aberrations
(3q-AML). Upon chromosomal rearrangement, G2DHE acquires
characteristics of a super-enhancer and causes
overexpression of EVI1 at 3q26.2. However, the transcription
factor (TF) complex of G2DHE remains poorly characterized.
The aim of this study was to unravel key components of
G2DHE-bound TFs involved in the deregulation of EVI1. We
have identified several CEBPA and RUNX1 binding sites to be
enriched and critical for G2DHE function in 3q-AML cells.
Using ChIP-SICAP (ChIP followed by selective isolation of
chromatin-associated proteins), a panel of chromatin
interactors of RUNX1 and CEBPA were detected in 3q-AML,
including PARP1 and IKZF1. PARP1 inhibition (PARPi) caused a
reduction of EVI1 expression and a decrease in EVI1-G2DHE
interaction frequency, highlighting the involvement of PARP1
in oncogenic super-enhancer formation. Furthermore, 3q-AML
cells were highly sensitive to PARPi and displayed
morphological changes with higher rates of differentiation
and apoptosis as well as depletion of CD34 + cells. In
summary, integrative analysis of the 3q-AML super-enhancer
complex identified CEBPA and RUNX1 associated proteins and
nominated PARP1 as a potential new therapeutic target in
EVI1 + 3q-AML.},
cin = {A380 / B230 / B370},
ddc = {610},
cid = {I:(DE-He78)A380-20160331 / I:(DE-He78)B230-20160331 /
I:(DE-He78)B370-20160331},
pnm = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
pid = {G:(DE-HGF)POF4-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:33911178},
doi = {10.1038/s41375-021-01235-z},
url = {https://inrepo02.dkfz.de/record/168557},
}