Analysis of gene expression during myc oncogene-induced lymphomagenesis in the bursa of Fabricius - PubMed (original) (raw)
Analysis of gene expression during myc oncogene-induced lymphomagenesis in the bursa of Fabricius
P E Neiman et al. Proc Natl Acad Sci U S A. 2001.
Abstract
The transcriptional effects of deregulated myc gene overexpression are implicated in tumorigenesis in a spectrum of experimental and naturally occurring neoplasms. In follicles of the chicken bursa of Fabricius, myc induction of B-cell neoplasia requires a target cell population present during early bursal development and progresses through preneoplastic transformed follicles to metastatic lymphomas. We developed a chicken immune system cDNA microarray to analyze broad changes in gene expression that occur during normal embryonic B-cell development and during myc-induced neoplastic transformation in the bursa. The number of mRNAs showing at least 3-fold change was greater during myc-induced lymphomagenesis than during normal development, and hierarchical cluster analysis of expression patterns revealed that levels of several hundred mRNAs varied in concert with levels of myc overexpression. A set of 41 mRNAs were most consistently elevated in myc-overexpressing preneoplastic and neoplastic cells, most involved in processes thought to be subject to regulation by Myc. The mRNAs for another cluster of genes were overexpressed in neoplasia independent of myc expression level, including a small subset with the expression signature of embryonic bursal lymphocytes. Overexpression of myc, and some of the genes overexpressed with myc, may be important for generation of preneoplastic transformed follicles. However, expression profiles of late metastatic tumors showed a large variation in concert with myc expression levels, and some showed minimal myc overexpression. Therefore, high-level myc overexpression may be more important in the early induction of these lymphomas than in maintenance of late-stage metastases.
Figures
Figure 1
Gene expression patterns during normal bursal development. (A) Chart of numbers of mRNAs showing at least 3-fold increases (red) or decreases (green) at embryonic days 15, 16, 18, and 21, compared with 2 weeks after hatching. (B) SOM (17) of 103 mRNAs showing at least 3-fold or greater changes at embryonic day 16 (E16) relative to 2-week posthatching bursa. The expression level of each gene was normalized to have a mean = 0 and SD =1 across time points. Each cluster exhibits an average pattern (blue) and SD for this average (red). Relative expression levels are shown on the_y_ axis and four time points (E15, E16, E18, E21) on the_x_ axis.
Figure 2
Relationship of level of _myc_-oncogene expression to change in expression of other mRNAs on the array. The number of mRNAs (y axis) showing 3-fold or greater increased (red) or decreased (green) expression, relative to the 2-week NB reference, for three TF preparations (squares), eight metastatic tumors (circles), and the DT40 cell line (diamonds). The fold increase in myc expression, determined on the array for each sample, is displayed on the x axis.
Figure 3
Gene expression profiles of _myc_-induced neoplastic change in the bursa. mRNAs showing at least a 3-fold change (approximately 800) in expression in at least 6 of 14 experimental samples were clustered. Groups of genes (y axis) with similar patterns of expression are indicated by vertical bars (A_–_E). DT40, DT40 cell line; MT, metastatic tumor. The fold increase in myc expression relative to normal bursa is shown in parentheses.
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