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Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation.

Ji H, Wu G, Zhan X, Nolan A, Koh C, De Marzo A, Doan HM, Fan J, Cheadle C, Fallahi M, Cleveland JL, Dang CV, Zeller KI - PLoS ONE (2011)

Bottom Line: Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types.Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes.Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America. hji@jhsph.edu

ABSTRACT
The functions of key oncogenic transcription factors independent of context have not been fully delineated despite our richer understanding of the genetic alterations in human cancers. The MYC oncogene, which produces the Myc transcription factor, is frequently altered in human cancer and is a major regulatory hub for many cancers. In this regard, we sought to unravel the primordial signature of Myc function by using high-throughput genomic approaches to identify the cell-type independent core Myc target gene signature. Using a model of human B lymphoma cells bearing inducible MYC, we identified a stringent set of direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified direct Myc targets in human embryonic stem cells (ESCs). We further document that a Myc core signature (MCS) set of target genes is shared in mouse and human ESCs as well as in four other human cancer cell types. Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types. Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes. Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression. Annotation of this gene signature reveals Myc's primordial function in RNA processing, ribosome biogenesis and biomass accumulation as its key roles in cancer and stem cells.

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Myc core target gene signature increases with the neoplastic switch to frank lymphoma in vivo.(A) Heatmap showing expression levels of the 51 Myc core target genes in wild-type, pre-malignant Eμ-Myc (4–6 week old) littermates and of Eμ-Myc lymphoma. (B) Clustering of human molecular Burkitt's lymphoma (mBL) and non-mBL samples using the 51 core target genes. (C) and (D) Heatmaps showing expression levels of B cell restricted (C) or ES cell restricted (D) upregulated Myc target genes in the mouse B cell samples. Green – low expression; Red – high expression.
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pone-0026057-g006: Myc core target gene signature increases with the neoplastic switch to frank lymphoma in vivo.(A) Heatmap showing expression levels of the 51 Myc core target genes in wild-type, pre-malignant Eμ-Myc (4–6 week old) littermates and of Eμ-Myc lymphoma. (B) Clustering of human molecular Burkitt's lymphoma (mBL) and non-mBL samples using the 51 core target genes. (C) and (D) Heatmaps showing expression levels of B cell restricted (C) or ES cell restricted (D) upregulated Myc target genes in the mouse B cell samples. Green – low expression; Red – high expression.

Mentions: We then studied the behavior of the MCS in vivo, in a transgenic model of Myc-driven lymphoma. We used the Eμ-Myc mouse model from which one can directly compare expression profiles of wild type versus Myc-expressing B220+ pre-malignant lymphocytes and also query differences in gene expression that ensue following the neoplastic switch to frank lymphoma [42]. Cluster analysis of expression of the 51 gene (of which we found murine probe sets for 48 genes) signature amongst wild type, premalignant Myc and malignant Myc B lymphocytes reveals a distinct increased expression of the MCS that correlates with the transformed malignant phenotype (Figure 6A). Further analysis showed that while 24.9% (6212 out of 24944) of genes on the microarray had increasing expression levels from wild type to premalignant Myc to malignant Myc B lymphocytes, 91.7% of the MCS (44 of the 48 genes) followed this pattern (Figure 6A, Methods S1), representing a much higher percentage (>3-fold enrichment). The overall correlation indicates that the MCS contributes to the malignant state. As predicted from analyses of P493-6 cells and hESCs, GSEA analysis established that the “Ribosome Pathway” gene set (http://www.broadinstitute.org/gsea/msigdb/cards/HSA03010_RIBOSOME.html) is also significantly enriched in premalignant Eμ-Myc B220+ B cells compared to their wild type counterparts (FDR = 0.26%, Figure S2). Finally, when 173 human mature aggressive B lymphoma samples were used for the clustering of the 51 gene MCS [43], molecular Burkitt's lymphoma (mBL) cases have distinctly higher MYC and MCS expression than the non-mBLcases (Figure 6B). With unsupervised clustering (Figure S3), all 44 mBL cases grouped together along with 10 out of 129 non-mBL cases, which have higher MCS expression. This observation suggests that some non-mBL cases in this series have higher MYC and MCS expression.


Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation.

Ji H, Wu G, Zhan X, Nolan A, Koh C, De Marzo A, Doan HM, Fan J, Cheadle C, Fallahi M, Cleveland JL, Dang CV, Zeller KI - PLoS ONE (2011)

Myc core target gene signature increases with the neoplastic switch to frank lymphoma in vivo.(A) Heatmap showing expression levels of the 51 Myc core target genes in wild-type, pre-malignant Eμ-Myc (4–6 week old) littermates and of Eμ-Myc lymphoma. (B) Clustering of human molecular Burkitt's lymphoma (mBL) and non-mBL samples using the 51 core target genes. (C) and (D) Heatmaps showing expression levels of B cell restricted (C) or ES cell restricted (D) upregulated Myc target genes in the mouse B cell samples. Green – low expression; Red – high expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198433&req=5

pone-0026057-g006: Myc core target gene signature increases with the neoplastic switch to frank lymphoma in vivo.(A) Heatmap showing expression levels of the 51 Myc core target genes in wild-type, pre-malignant Eμ-Myc (4–6 week old) littermates and of Eμ-Myc lymphoma. (B) Clustering of human molecular Burkitt's lymphoma (mBL) and non-mBL samples using the 51 core target genes. (C) and (D) Heatmaps showing expression levels of B cell restricted (C) or ES cell restricted (D) upregulated Myc target genes in the mouse B cell samples. Green – low expression; Red – high expression.
Mentions: We then studied the behavior of the MCS in vivo, in a transgenic model of Myc-driven lymphoma. We used the Eμ-Myc mouse model from which one can directly compare expression profiles of wild type versus Myc-expressing B220+ pre-malignant lymphocytes and also query differences in gene expression that ensue following the neoplastic switch to frank lymphoma [42]. Cluster analysis of expression of the 51 gene (of which we found murine probe sets for 48 genes) signature amongst wild type, premalignant Myc and malignant Myc B lymphocytes reveals a distinct increased expression of the MCS that correlates with the transformed malignant phenotype (Figure 6A). Further analysis showed that while 24.9% (6212 out of 24944) of genes on the microarray had increasing expression levels from wild type to premalignant Myc to malignant Myc B lymphocytes, 91.7% of the MCS (44 of the 48 genes) followed this pattern (Figure 6A, Methods S1), representing a much higher percentage (>3-fold enrichment). The overall correlation indicates that the MCS contributes to the malignant state. As predicted from analyses of P493-6 cells and hESCs, GSEA analysis established that the “Ribosome Pathway” gene set (http://www.broadinstitute.org/gsea/msigdb/cards/HSA03010_RIBOSOME.html) is also significantly enriched in premalignant Eμ-Myc B220+ B cells compared to their wild type counterparts (FDR = 0.26%, Figure S2). Finally, when 173 human mature aggressive B lymphoma samples were used for the clustering of the 51 gene MCS [43], molecular Burkitt's lymphoma (mBL) cases have distinctly higher MYC and MCS expression than the non-mBLcases (Figure 6B). With unsupervised clustering (Figure S3), all 44 mBL cases grouped together along with 10 out of 129 non-mBL cases, which have higher MCS expression. This observation suggests that some non-mBL cases in this series have higher MYC and MCS expression.

Bottom Line: Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types.Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes.Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America. hji@jhsph.edu

ABSTRACT
The functions of key oncogenic transcription factors independent of context have not been fully delineated despite our richer understanding of the genetic alterations in human cancers. The MYC oncogene, which produces the Myc transcription factor, is frequently altered in human cancer and is a major regulatory hub for many cancers. In this regard, we sought to unravel the primordial signature of Myc function by using high-throughput genomic approaches to identify the cell-type independent core Myc target gene signature. Using a model of human B lymphoma cells bearing inducible MYC, we identified a stringent set of direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified direct Myc targets in human embryonic stem cells (ESCs). We further document that a Myc core signature (MCS) set of target genes is shared in mouse and human ESCs as well as in four other human cancer cell types. Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types. Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes. Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression. Annotation of this gene signature reveals Myc's primordial function in RNA processing, ribosome biogenesis and biomass accumulation as its key roles in cancer and stem cells.

Show MeSH
Related in: MedlinePlus