Analysis of gene expression during myc oncogene-induced lymphomagenesis in the bursa of Fabricius

doi:10.1073/pnas.111144898

Analysis of gene expression during myc oncogene-induced lymphomagenesis in the bursa of Fabricius

^*Divisions of Basic Sciences and Human Biology, Fred Hutchinson Cancer Research Center and the Departments of Medicine and Pathology, University of Washington, 1100 Fairview Avenue North, Seattle, WA 98109-1024; ^‡Huntsman Cancer Institute and Section of Oncology, Department of Medicine, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112; and ^§Department of Animal and Food Sciences, University of Delaware, Newark, DE 19717

Communicated by Robert N. Eisenman, Fred Hutchinson Cancer Research Center, Seattle, WA (received for review January 23, 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.

Footnotes

↵ † To whom reprint requests should be addressed. E-mail: pneiman{at}fhcrc.org.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (for accession nos., see Table 2, which is published as supplemental data on the PNAS web site, www.pnas.org).
↵ ¶ Details of the Pat library clones used are found in Array 4 at the University of Delaware Chick EST web site: http://udgenome.ags.udel.chickest.array.htm.
Abbreviations:

TF,

transformed bursal follicle;

HB1,

recovered avian myelocytomatosis virus strain MC-29-HB1;

SOM,

self-organizing map;

NB,

normal 2-week posthatching bursa