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Theophylline Induced Differentiation Provides Direct Evidence for the Deregulation of c-myc in Burkitt's Lymphoma and Suggests Participation of Immunoglobulin Enhancer Sequences¹

Pediatric Branch, Clinical Oncology Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20892 [J. T. S., L. M. N., I. T. M.]; Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101[J. T. S., H. E. S., L. S. W.]; and Department of Pediatrics, University of Tennessee, College of Medicine, Memphis, Tennessee 38103 [J. T. S.]

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. Matsul, 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-µ 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-µ 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. Thus, in JD38, the c-myc genes adjacent to the immunoglobulin constant region are abnormally regulated, while the first exon remaining on chromosome 8 is regulated as is the normal c-myc gene in other non-BL differentiation-induction model systems. These data directly demonstrate that c-myc is abnormally regulated in BL and strongly support the hypothesis that the translocated c-myc gene is regulated by sequences present in the juxtaposed immunoglobulin gene. Furthermore, we propose that the structural alterations present in the translocated c-myc allele are permissive for immunoglobulin enhancer usurpation of transcriptional control.

¹ Supported in part by Grants CA-20180 and CA-21765 from the National Cancer Institute, the American Lebanese Syrian Associated Charities, and the Cancer Research Foundation of America.

Received 7/13/92. Accepted 10/20/92.