Abstract
BackgroundAmplification of MYCN (N-Myc) oncogene has been reported as a frequent event and a poor prognostic marker in human acute myeloid leukemia (AML). The molecular mechanisms and transcriptional networks by which MYCN exerts its influence in AML are largely unknown.Methodology/Principal FindingsWe introduced murine MYCN gene into embryonic zebrafish through a heat-shock promoter and established the stable germline Tg(MYCN:HSE:EGFP) zebrafish. N-Myc downstream regulated gene 1 (NDRG1), negatively controlled by MYCN in human and functionally involved in neutrophil maturation, was significantly under-expressed in this model. Using peripheral blood smear detection, histological section and flow cytometric analysis of single cell suspension from kidney and spleen, we found that MYCN overexpression promoted cell proliferation, enhanced the repopulating activity of myeloid cells and the accumulation of immature hematopoietic blast cells. MYCN enhanced primitive hematopoiesis by upregulating scl and lmo2 expression and promoted myelopoiesis by inhibiting gata1 expression and inducing pu.1, mpo expression. Microarray analysis identified that cell cycle, glycolysis/gluconeogenesis, MAPK/Ras, and p53-mediated apoptosis pathways were upregulated. In addition, mismatch repair, transforming and growth factor β (TGFβ) were downregulated in MYCN-overexpressing blood cells (p<0.01). All of these signaling pathways are critical in the proliferation and malignant transformation of blood cells.Conclusion/SignificanceThe above results induced by overexpression of MYCN closely resemble the main aspects of human AML, suggesting that MYCN plays a role in the etiology of AML. MYCN reprograms hematopoietic cell fate by regulating NDRG1 and several lineage-specific hematopoietic transcription factors. Therefore, this MYCN transgenic zebrafish model facilitates dissection of MYCN-mediated signaling in vivo, and enables high-throughput scale screens to identify the potential therapeutic targets.
Highlights
Myc was first discovered as the oncogene of avian leukemogenic retroviruses, and later found translocated in human lymphomas
We report here a MYCN transgenic zebrafish model with a phenotype that recapitulates main aspects of human acute myeloid leukemia (AML) such as distorted proliferation, metabolic disturbance, increased myeloid cells and their precursors accumulation in peripheral circulation, spleen and kidney marrow, suggesting that MYCN plays a role in the etiology of AML
We demonstrated that MYCN reprograms hematopoietic cell fate by regulating N-Myc downstream regulated gene 1 (NDRG1) and several lineage-specific hematopoietic transcription factors in vivo
Summary
Myc was first discovered as the oncogene of avian leukemogenic retroviruses, and later found translocated in human lymphomas. Amplification of MYCN is frequently found in hematologic malignancies such as lymphoma and acute myeloid leukemia (AML), considered as a well-established poor prognostic marker in these diseases [1,2,3]. The authors demonstrated that overexpression of MYCN rapidly caused acute myeloid leukemia in Mice [4]. The role of MYCN expression in the regulation of hematopoiesis and the mechanisms by which it acts to promote an aggressive maglinant phenotype remain largely unknown, and generation of transgenic offspring was not possible. Amplification of MYCN (N-Myc) oncogene has been reported as a frequent event and a poor prognostic marker in human acute myeloid leukemia (AML). The molecular mechanisms and transcriptional networks by which MYCN exerts its influence in AML are largely unknown
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