Document Detail


Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma.
MedLine Citation:
PMID:  17710228     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.
Authors:
Liping Song; Tasnim Ara; Hong-Wei Wu; Chan-Wook Woo; C Patrick Reynolds; Robert C Seeger; Yves A DeClerck; Carol J Thiele; Richard Sposto; Leonid S Metelitsa
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  117     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-09-05     Completed Date:  2007-10-23     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2702-12     Citation Subset:  AIM; IM    
Affiliation:
Division of Hematology-Oncology, Department of Pediatrics, Childrens Hospital Los Angeles (CHLA), Los Angeles, California 90027, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Marrow / pathology
Cell Movement*
Cells, Cultured
Chemokine CCL2 / metabolism
Female
Gene Expression Regulation
Humans
Mice
Mice, SCID
Neoplasm Metastasis / pathology
Neuroblastoma / genetics,  metabolism*,  pathology*
Nuclear Proteins / genetics,  metabolism*
Oncogene Proteins / genetics,  metabolism*
Phenotype
Promoter Regions, Genetic / genetics
Protein Binding
RNA Interference
STAT3 Transcription Factor / metabolism
T-Lymphocytes, Regulatory / cytology*,  metabolism*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
CA116548/CA/NCI NIH HHS; CA60104/CA/NCI NIH HHS; CA81403/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Chemokine CCL2; 0/MYCN protein, human; 0/Nuclear Proteins; 0/Oncogene Proteins; 0/STAT3 Transcription Factor
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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