Amplification at 7q22 targets cyclin-dependent kinase 6 in T-cell lymphoma.
Recurrent chromosomal aberrations in hematopoietic tumors target genes involved in pathogenesis. Their identification and functional characterization are therefore important for the establishment of rational therapies. Here, we investigated genomic amplification at 7q22 in the T-cell lymphoma cell line SU-DHL-1 belonging to the subtype of anaplastic large-cell lymphoma (ALCL). Cytogenetic analysis mapped this amplicon to 86-95 Mb. Copy-number determination quantified the amplification level at 5- to 6-fold. Expression analysis of genes located within this region identified cyclin-dependent kinase 6 (CDK6) as a potential amplification target. In comparison with control cell lines, SU-DHL-1 expressed considerably higher levels of CDK6. Functionally, SU-DHL-1 cells exhibited reduced sensitivity to rapamycin treatment, as indicated by cell growth and cell cycle analysis. Rapamycin reportedly inhibits degradation of the CDK inhibitor p27 with concomitant downregulation of cyclin D3, implying a proliferative advantage for CDK6 overexpression. Amplification of the CDK6 locus was analyzed in primary T-cell lymphoma samples and, while detected infrequently in those classified as ALCL (1%), was detected in 23% of peripheral T-cell lymphomas not otherwise specified. Taken together, analysis of the 7q22 amplicon identified CDK6 as an important cell cycle regulator in T-cell lymphomas, representing a novel potential target for rational therapy.
Nagel
S
S
Department of Human and Animal Cell Cultures, DSMZ, Braunschweig, Germany. sna@dsmz.de
Leich
E
E
Quentmeier
H
H
Meyer
C
C
Kaufmann
M
M
Drexler
H G
HG
Zettl
A
A
Rosenwald
A
A
MacLeod
R A F
RA
D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D020732:Cytogenetic Analysis; D004351:Drug Resistance / Q000235:genetics; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016411:Lymphoma, T-Cell, Peripheral / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D051361:Cyclin-Dependent Kinase 6; D020123:Sirolimus