Theophylline induced differentiation provides direct evidence for the deregulation of c-myc in Burkitt's lymphoma and suggests participation of immunoglobulin enhancer sequences.
Most of the evidence that supports the hypothesis that the c-myc gene is abnormally regulated in Burkitt's lymphoma (BL) is indirect. The putative abnormal expression of c-myc is likely, at least in part, to be a consequence of the usurpation of its regulatory sequences by immunoglobulin enhancer elements, which are invariably juxtaposed to c-myc by the translocations associated with this tumor (C. M. Croce, J. Erikson, A. Ar-Rushdi, D. Aden, and K. Nishikura, Proc. Natl. Acad. Sci. USA, 81: 3170-3174, 1984). We have developed a differentiation induction model system to examine this issue more directly. In a variety of non-BL cell lines, differentiation induction results in the down-regulation of c-myc (G. P. Studzinski, A. K. Bhandal, and Z. S. Brelvi, Proc. Soc. Exp. Biol. Med., 179: 288-295, 1985; Y. Matsui, R. Takahasi, K. Minara, T. Nakagawa, T. Koizumi, Y. Nakao, T. Sugiyama, and T. Fugita, Cancer Res., 49: 1366-1371, 1985; T. Mitchell, E. Sariban, and D. Kufe, Mol. Pharmacol., 30: 398-402, 1986; Z. S. Brelvi, and G. P. Studzinski, J. Cell. Physiol., 128: 171-179, 1986). Since BL is of B-cell origin, differentiation is associated with persistent or increased expression of immunoglobulin genes. Therefore, if c-myc and c-mu are coregulated in BL via immunoglobulin enhancer sequences, persistent or increased expression of the c-myc gene, rather than down-regulation, should occur in differentiated BL cells. Differentiation was induced in four BL cell lines with theophylline (7 x 10(-3) M), and mRNA was examined by Northern blot analysis. In all four BL lines studied (JD38, AG876, KK124, and Daudi), there was persistent or increased expression of both c-mu and c-myc genes (detected with a third exon c-myc probe), in contrast to the decreased expression of the c-myc gene observed in the three Epstein-Barr virus transformed lines studied (A3317, TC84, and CB34). In the BL cell line, JD38, the c-myc gene is truncated (the second and third exons are translocated to chromosome 14 while the first exon remains on chromosome 8). In this line, we demonstrated that theophylline induced differentiation results in down-regulation of the first exon while the level of expression of the translocated second and third exons remains unchanged or increases.(ABSTRACT TRUNCATED AT 400 WORDS)
Sandlund
J T
JT
Pediatric Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Neckers
L M
LM
Schneller
H E
HE
Woodruff
L S
LS
Magrath
I T
IT
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005803:Genes, Immunoglobulin / Q000235:genetics*; D016259:Genes, myc / Q000187:drug effects / Q000235:genetics*; D006207:Half-Life; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D013806:Theophylline / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D013806:Theophylline