Myeloid transformation by MLL-ENL depends strictly on C/EBP.
Life Sci Alliance
; 4(1)2021 01.
Article
in En
| MEDLINE
| ID: mdl-33144337
Chromosomal rearrangements of the mixed-lineage leukemia gene MLL1 are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the epigenetic basis for myelomonocytic leukemia stemness and transformation by MLL-type oncoproteins. Previously, it was shown that the establishment of murine myelomonocytic MLL-ENL transformation, but not its maintenance, depends on the transcription factor C/EBPα, suggesting an epigenetic hit-and-run mechanism of MLL-driven oncogenesis. Here, we demonstrate that compound deletion of Cebpa/Cebpb almost entirely abrogated the growth and survival of MLL-ENL-transformed cells. Rare, slow-growing, and apoptosis-prone MLL-ENL-transformed escapees were recovered from compound Cebpa/Cebpb deletions. The escapees were uniformly characterized by high expression of the resident Cebpe gene, suggesting inferior functional compensation of C/EBPα/C/EBPß deficiency by C/EBPε. Complementation was augmented by ectopic C/EBPß expression and downstream activation of IGF1 that enhanced growth. Cebpe gene inactivation was accomplished only in the presence of complementing C/EBPß, but not in its absence, confirming the Cebpe dependency of the Cebpa/Cebpb double knockouts. Our data show that MLL-transformed myeloid cells are dependent on C/EBPs during the initiation and maintenance of transformation.
Full text:
1
Collection:
01-internacional
Health context:
2_ODS3
/
6_ODS3_enfermedades_notrasmisibles
/
7_ODS3_muertes_prevenibles_nacidos_ninos
Database:
MEDLINE
Main subject:
Leukemia, Myeloid, Acute
/
Oncogene Proteins, Fusion
/
Cell Transformation, Neoplastic
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CCAAT-Enhancer-Binding Proteins
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CCAAT-Enhancer-Binding Protein-alpha
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CCAAT-Enhancer-Binding Protein-beta
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Granulocyte Precursor Cells
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Myeloid-Lymphoid Leukemia Protein
Limits:
Animals
/
Humans
Language:
En
Journal:
Life Sci Alliance
Year:
2021
Document type:
Article