Abstract
MYC proto-oncogene family including c-myc and n-myc (MYCN) are critical for normal cell development and tumorigenesis. Overexpression of c-myc causes acute erythroleukemia in vivo. However, the role of MYCN in acute erythroleukemia remains poorly understood. In this study, we found that the patients with erythroleukemia showed higher expression of MYCN than normal controls. In vitro experiments, knockdown of MYCN resulted in decreased cell proliferation, elevated autonomously cell apoptosis and increased P21-mediated cell senescence. On the contrary, overexpression of MYCN obviously promoted cell proliferation, and induced erythroid differentiation block and apoptosis resistance to cytotoxic agent. Further gene microarray and functional analysis revealed that EZH2 is a target of MYCN. Knockdown of MYCN inhibited the expression of EZH2, and then activated p21 expression through removal of H3K27me3 at the p21 promoter. Overexpression of ezh2 could antagonize the p21 activation caused by MYCN knockdown. In addition, Aurora inhibitor MLN8237 inhibited the proliferation of erythroleukemia cells through repression of MYCN/EZH2 axis, whereas it minimally affected the normal hematopoietic cells. In conclusion, MYCN contributes to the malignant characteristics of erythroleukemia through EZH2-meidated epigenetic repression of p21. MYCN may serve as a therapy target for the patients with acute erythroleukemia.
Highlights
(MYCN) and l-myc (MYCL), are critical for normal cell development and proliferation.[1]
Considering the pivotal role of MYC in erythroleukemia development, we explored the biological function of MYCN in erythroleukemia cell lines HEL and K562
MYCN is overexpressed in the patients with erythroleukemia
Summary
(MYCN) and l-myc (MYCL), are critical for normal cell development and proliferation.[1] Abnormal expression of MYC family promotes the tumorigenesis in multiple human cancers.[2] MYC is one of the most common oncogenes in human cancers, and frequently associated to lymphoma and lymphoblastic leukemia.[2,3] Increasing evidence has showed that MYC has a driving role in myeloid malignancies.[4,5,6]. Transgenic MYCN expression induced lymphoma in mouse model.[13] Overexpression of MYCN was observed in some patients with acute myeloid leukemia.[14] Leukemia mouse model showed elevated MYCN expression.[15] All these studies suggest that MYCN may be vitally critical for leukomogenesis. The mechanism of MYCN in maintenance of malignant characteristic of leukemia cells was investigated by cell functional assays, gene microarray, and chromatin immunoprecipitation
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