Journal Article

DKFZ-2021-00974

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia.

Kiehlmeier, S. (First author)DKFZ* ; Rafiee, M.-R. ; Bakr, A. M. A.DKFZ* ; Mika, J.DKFZ* ; Kruse, S.DKFZ* ; Müller, J.DKFZ* ; Schweiggert, S.DKFZ* ; Herrmann, C. ; Sigismondo, G.DKFZ* ; Schmezer, P.DKFZ* ; Krijgsveld, J.DKFZ* ; Gröschel, S. (Last author)DKFZ*

2021
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41375-021-01235-z

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.

Note: #EA:A380#LA:A380# / 2021 Nov;35(11):3127-3138

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Contributing Institute(s):

1. NWG Molekulare Leukämogenese (A380)
2. B230 Proteomik (B230)
3. Epigenomik (B370)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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