Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia.
Leukemia
; 35(11): 3127-3138, 2021 11.
Article
de En
| MEDLINE
| ID: mdl-33911178
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Réarrangement des gènes
/
Leucémie aigüe myéloïde
/
Régulation de l'expression des gènes dans la leucémie
/
Éléments activateurs (génétique)
/
Facteur de transcription GATA-2
/
Sous-unité alpha 2 du facteur CBF
/
Protéine du locus du complexe MDS1 et EVI1
Type d'étude:
Diagnostic_studies
/
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Leukemia
Sujet du journal:
HEMATOLOGIA
/
NEOPLASIAS
Année:
2021
Type de document:
Article
Pays d'affiliation:
Allemagne