Deregulation of the proto-oncogene c-myc through t(8;22) translocation in Burkitt's lymphoma.
In Burkitt's lymphoma (BL) cells the proto-oncogene c-myc is juxtaposed to one of the immunoglobulin (Ig) loci on chromosomes 2, 14, or 22. The c-myc gene becomes transcriptionally activated as a consequence of the chromosomal translocation and shows preferential usage of promoter P1 over P2, a phenomenon referred to as promoter shift. In order to define the responsible regulatory elements within the Ig lambda locus, we studied the effect of the human Ig lambda enhancer (HuE lambda) on c-myc expression after stable transfection into BL cells. A 12 kb genomic fragment encompassing HuE lambda, but not HuE lambda alone, strongly activated c-myc expression and induced the promoter shift. To identify additional elements involved in c-myc deregulation, we mapped DNaseI hypersensitive sites within the 12 kb lambda fragment on the construct. Besides one hypersensitive site corresponding to HuE lambda, three additional sites were detected. Two of these elements displayed enhancer activity after transient transfection. The third element did not activate c-myc transcription, but was required for full c-myc activation and promoter shift. Deletion analyses of the c-myc promoter identified the immediate promoter region as sufficient for activation by the Ig lambda. locus, but also revealed that induction of the promoter shift requires additional upstream elements.
Gerbitz
A
A
Dana Farber Cancer Institute, Pediatric Oncology, Boston, Massachusetts 02115, USA.
Mautner
J
J
Geltinger
C
C
Hörtnagel
K
K
Christoph
B
B
Asenbauer
H
H
Klobeck
G
G
Polack
A
A
Bornkamm
G W
GW
D001665:Binding Sites; D002051:Burkitt Lymphoma / Q000235:genetics*; D002087:Butyrates / Q000494:pharmacology; D002892:Chromosomes, Human, Pair 22; D002898:Chromosomes, Human, Pair 8; D003850:Deoxyribonuclease I; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D014162:Transfection; D014178:Translocation, Genetic
D002087:Butyrates; D007146:Immunoglobulin lambda-Chains; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D003850:Deoxyribonuclease I