A C/ebpα isoform specific differentiation program in immortalized myelocytes.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
15
05
2023
accepted:
25
07
2023
revised:
18
07
2023
medline:
28
8
2023
pubmed:
3
8
2023
entrez:
2
8
2023
Statut:
ppublish
Résumé
The transcription factor CCAAT-enhancer binding factor alpha (C/ebpα) is a master controller of myeloid differentiation that is expressed as long (p42) and short (p30) isoform. Mutations within the CEBPA gene selectively deleting p42 are frequent in human acute myeloid leukemia. Here we investigated the individual genomics and transcriptomics of p42 and p30. Both proteins bound to identical sites across the genome. For most targets, they induced a highly similar transcriptional response with the exception of a few isoform specific genes. Amongst those we identified early growth response 1 (Egr1) and tribbles1 (Trib1) as key targets selectively induced by p42 that are also underrepresented in CEBPA-mutated AML. Egr1 executed a program of myeloid differentiation and growth arrest. Oppositely, Trib1 established a negative feedback loop through activation of Erk1/2 kinase thus placing differentiation under control of signaling. Unexpectedly, differentiation elicited either by removal of an oncogenic input or by G-CSF did not peruse C/ebpα as mediator but rather directly affected the cell cycle core by upregulation of p21/p27 inhibitors. This points to functions downstream of C/ebpα as intersection point where transforming and differentiation stimuli converge and this finding offers a new perspective for therapeutic intervention.
Identifiants
pubmed: 37532789
doi: 10.1038/s41375-023-01989-8
pii: 10.1038/s41375-023-01989-8
pmc: PMC10457184
doi:
Substances chimiques
Protein Isoforms
0
CCAAT-Enhancer-Binding Protein-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1850-1859Informations de copyright
© 2023. The Author(s).
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