C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor.
Aged
Alleles
Animals
CCAAT-Enhancer-Binding Protein-alpha
/ genetics
Cell Differentiation
Cell Lineage
Cell Transformation, Neoplastic
/ genetics
Disease Models, Animal
Erythroid Precursor Cells
/ metabolism
Female
GATA1 Transcription Factor
/ genetics
GATA2 Transcription Factor
/ genetics
Humans
Leukemia, Erythroblastic, Acute
/ genetics
Male
Mice
Mice, Inbred C57BL
Middle Aged
Mutation
Neutrophils
/ metabolism
Zinc Fingers
CEBPA
GATA2
acute erythroid leukemia
acute myeloid leukemia
chromatin accessibility
leukemia-initiating cell
lineage priming
oncogene co-operation
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
11 05 2020
11 05 2020
Historique:
received:
18
12
2018
revised:
12
01
2020
accepted:
27
03
2020
pubmed:
25
4
2020
medline:
4
11
2020
entrez:
25
4
2020
Statut:
ppublish
Résumé
Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia.
Identifiants
pubmed: 32330454
pii: S1535-6108(20)30162-8
doi: 10.1016/j.ccell.2020.03.022
pmc: PMC7218711
pii:
doi:
Substances chimiques
CCAAT-Enhancer-Binding Protein-alpha
0
GATA1 Transcription Factor
0
GATA1 protein, human
0
GATA2 Transcription Factor
0
GATA2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
690-704.e8Subventions
Organisme : Medical Research Council
ID : MC_UU_00016/11
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M00919X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U137961146
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T015055/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12025
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900892
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00016/7
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1000729
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L008963/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/7
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/11
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0902418
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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