ZFIN ID: ZDB-PUB-160428-8
CREB engages C/EBPδ to initiate leukemogenesis
Tregnago, C., Manara, E., Zampini, M., Bisio, V., Borga, C., Bresolin, S., Aveic, S., Germano, G., Basso, G., Pigazzi, M.
Date: 2016
Source: Leukemia   30(9): 1887-96 (Journal)
Registered Authors: Aveic, Sanja
Keywords: none
Microarrays: 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
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.