|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.
|Source:||Leukemia 30(9): 1887-96 (Journal)|
|PubMed:||27118402 Full text @ Leukemia|
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.
ABSTRACTcAMP 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.