CREB engages C/EBPδ to initiate leukemogenesis

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• cAMP response element binding protein (CREB) is a proto-oncogene often overexpressed in acute myeloid leukemia (AML).
• The precise role and downstream signaling of CREB in AML pathogenesis remain incompletely understood.
• Whether CREB overactivation alone can induce leukemia is still debated.

Purpose of the Study:

• To investigate the pathogenetic role of CREB in acute myeloid leukemia (AML) using a zebrafish model.
• To elucidate the downstream signaling pathways regulated by CREB in myeloid leukemia.
• To identify potential therapeutic targets within the CREB-mediated signaling cascade.

Main Methods:

• Generation of a zebrafish model with myeloid lineage-specific CREB overexpression.
• Analysis of hematopoietic development and differentiation in CREB-zebrafish.
• Gene expression profiling to identify CREB targets homologous to human AML.
• Functional studies involving CREB and CCAAT-enhancer-binding protein-δ (C/EBPδ) manipulation.
• Correlation of C/EBPδ overexpression with clinical data in pediatric AML patients.

Main Results:

• CREB overexpression in zebrafish led to aberrant hematopoiesis and monocytic leukemia in 79% of adult fish.
• A signature of 20 differentially expressed CREB targets, homologous to human AML, was identified.
• CREB increased C/EBPδ levels, causing myeloid differentiation arrest; silencing this axis restored differentiation.
• C/EBPδ overexpression identified a high-risk pediatric AML subset with monocytic differentiation block and aggressive signatures.

Conclusions:

• The CREB-C/EBPδ axis is aberrantly activated in AML, disrupting myeloid cell differentiation and contributing to disease onset.
• This study provides a novel zebrafish model for high-throughput drug screening to improve AML treatment.
• Targeting the CREB-C/EBPδ pathway represents a potential therapeutic strategy for specific AML subsets.