Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma.
A synergistic interaction of Bcl-2 and c-Myc plays a role in lymphomagenesis in mice and in some patients as well. Progression of follicular lymphoma to a more aggressive lymphoma is seen in the majority of patients, and approximately 10% of the transformed lymphomas have a translocation of c-myc in addition to the translocation of bcl-2 found in the original follicular lymphoma. We investigated whether transcriptional deregulation of bcl-2 and c-myc could be examined in primary lymphoma cells by in vivo footprinting and in vitro protein-DNA binding studies. A matched pair of follicular and transformed lymphoma samples was examined. The transformed lymphoma had acquired a translocation of c-myc into the immunoglobulin heavy chain locus. High levels of bcl-2 expression were observed in both the follicular and transformed lymphomas, whereas the expression of c-myc was low in the follicular lymphoma and increased in the transformed lymphoma. In vivo footprint analysis revealed that a CRE site and a Cdx site in the bcl-2 promoter were occupied on the translocated alleles but not on the normal alleles in both the follicular and transformed lymphomas. Two nuclear factor kappaB sites were occupied on the translocated c-myc allele in the transformed lymphoma. Gel shift analysis revealed that these proteins bound to their respective sites in the bcl-2 or c-myc promoter. There was no evidence that the presence of one of the translocations in the immunoglobulin heavy chain locus influenced the expression of the other translocated gene.
Arcinas
M
M
Center for Molecular Biology in Medicine, Palo Alto Veterans Affairs Medical Center and Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Heckman
C A
CA
Mehew
J W
JW
Boxer
L M
LM
D000483:Alleles; D001665:Binding Sites; D015152:Blotting, Northern; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018983:DNA Footprinting; D018450:Disease Progression; D016521:Electrophoresis, Gel, Pulsed-Field; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2 / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000235:genetics*; D014178:Translocation, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B