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Stem cell biology

CREB engages C/EBPδ to initiate leukemogenesis

Leukemia volume 30, pages 1887–1896 (2016)Cite this article

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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 whether such overactivation alone is able to induce leukemia as its pathogenetic downstream signaling is still unclear. 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 CCAAT-enhancer-binding protein-δ (C/EBPδ) levels to cause 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 unveils 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.

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Acknowledgements

We thank Dr Patrizia Porazzi for zebrafish manipulation, Dr Benedetta Accordi and Dr Valentina Serafin for RPPA analysis, Dr Chiara Frasson for cell sorting and Dr Luca Persano for tissue sectioning. This work was supported by grants from Cariparo, IRP-Istituto di Ricerca Pediatrica Città della Speranza Padova and Università degli Studi di Padova.

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Authors and Affiliations

  1. Women and Child Health Department, Hematology-Oncology Clinic, University of Padova, Padova, Italy

    C Tregnago, V Bisio, C Borga, S Bresolin, G Basso & M Pigazzi

  2. Istituto di Ricerca Pediatrica (IRP), Padova, Italy

    E Manara, M Zampini, S Aveic & G Germano

  3. Pediatric Hematology-Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    C Borga

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  1. C Tregnago
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Correspondence to M Pigazzi.

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Tregnago, C., Manara, E., Zampini, M. et al. CREB engages C/EBPδ to initiate leukemogenesis. Leukemia 30, 1887–1896 (2016). https://doi.org/10.1038/leu.2016.98

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