PUBLICATION
CREB engages C/EBPδ to initiate leukemogenesis
- Authors
- Tregnago, C., Manara, E., Zampini, M., Bisio, V., Borga, C., Bresolin, S., Aveic, S., Germano, G., Basso, G., Pigazzi, M.
- ID
- ZDB-PUB-160428-8
- Date
- 2016
- Source
- Leukemia 30(9): 1887-96 (Journal)
- Registered Authors
- Aveic, Sanja
- Keywords
- none
- Datasets
- GEO:GSE71270
- MeSH Terms
-
- Animals
- CCAAT-Enhancer-Binding Protein-delta/metabolism*
- Carcinogenesis*
- Cell Differentiation
- Cell Lineage
- Cyclic AMP Response Element-Binding Protein/genetics
- Cyclic AMP Response Element-Binding Protein/metabolism*
- Disease Models, Animal
- Hematopoiesis
- Leukemia, Myeloid, Acute/etiology*
- Monocytes
- Myeloid Cells
- Zebrafish
- PubMed
- 27118402 Full text @ Leukemia
Citation
Tregnago, C., Manara, E., Zampini, M., Bisio, V., Borga, C., Bresolin, S., Aveic, S., Germano, G., Basso, G., Pigazzi, M. (2016) CREB engages C/EBPδ to initiate leukemogenesis. Leukemia. 30(9):1887-96.
Abstract
cAMP response element binding protein (CREB) is frequently overexpressed in acute myeloid leukemia (AML) and acts as a proto-oncogene; however, it is still debated if such overactivation alone is able to induce leukemia since its pathogenetic downstream signaling is still unclear. Hence, we generated a zebrafish model overexpressing CREB in the myeloid lineage, which showed an aberrant regulation of primitive hematopoiesis, and in 79% of adult CREB-zebrafish a block of myeloid differentiation, triggering to a monocytic leukemia akin the human counterpart. Gene expression analysis of CREB-zebrafish revealed a signature of 20 differentially expressed human homologous CREB targets in common with pediatric AML. Among them, we demonstrated that CREB overexpression increased C/EBPδ levels to cause the myeloid differentiation arrest, and the silencing of CREB-C/EBPδ axis restored myeloid terminal differentiation. Then, C/EBPδ overexpression was found to identify a subset of pediatric AML affected by a block of myeloid differentiation at monocytic stage who presented a significant higher relapse risk and the enrichment of aggressive signatures. Finally, this study unveil the aberrant activation of CREB-C/EBPδ axis concurring to AML onset by disrupting the myeloid cell differentiation process. We provide a novel in vivo model to perform high-throughput drug screening for AML cure improvement.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping