CREB engages C/EBPδ to initiate leukemogenesis.
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.
Women and Child Health Department, Hematology-Oncology Clinic, University of Padova, Padova, Italy.
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Tregnago
Istituto di Ricerca Pediatrica (IRP), Padova, Italy.
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0000-0002-1176-3359
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Manara
Istituto di Ricerca Pediatrica (IRP), Padova, Italy.
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Zampini
Women and Child Health Department, Hematology-Oncology Clinic, University of Padova, Padova, Italy.
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Bisio
Women and Child Health Department, Hematology-Oncology Clinic, University of Padova, Padova, Italy.|Pediatric Hematology-Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Borga
Women and Child Health Department, Hematology-Oncology Clinic, University of Padova, Padova, Italy.
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Bresolin
Istituto di Ricerca Pediatrica (IRP), Padova, Italy.
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Aveic
Istituto di Ricerca Pediatrica (IRP), Padova, Italy.
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Germano
Women and Child Health Department, Hematology-Oncology Clinic, University of Padova, Padova, Italy.
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Basso
Women and Child Health Department, Hematology-Oncology Clinic, University of Padova, Padova, Italy.
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Pigazzi
D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism*; D063646:Carcinogenesis; D002454:Cell Differentiation; D019070:Cell Lineage; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006410:Hematopoiesis; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D009000:Monocytes; D022423:Myeloid Cells; D000090063:Proto-Oncogene Mas; D015027:Zebrafish
D017362:Cyclic AMP Response Element-Binding Protein; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051743:CCAAT-Enhancer-Binding Protein-delta