High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease.
Anaplastic large cell lymphoma (ALCL) with t(2;5)(p23;q35) and Hodgkin disease (HD) share many cellular features, including expression of CD30. We compared gene expression profiles of 4 ALCL (Karpas 299, SU-DHL-1, DEL, SR-786) and 3 HD cell lines and found that BCL3, which encodes a nuclear protein belonging to the I kappa B family of inhibitors of nuclear factor-kappa B (NF-kappa B) transcriptional factors, was expressed at higher levels in ALCL than HD. Northern and Western blotting analyses confirmed the high-level expression of BCL3 in ALCL at both mRNA and protein levels. We established a real-time reverse transcriptase-mediated polymerase chain reaction assay to measure the BCL3 mRNA level and found a predominant level of BCL3 expression in t(2;5)(+) ALCL; the levels of cell lines and clinical materials were comparable to or higher than that of a B-cell chronic lymphocytic leukemia carrying t(14;19)(q32;q13). Southern blotting and fluorescence in situ hybridization disclosed that the BCL3 gene copies were amplified in SU-DHL-1, whereas Karpas 299 carried 4 BCL3 gene loci. The BCL3 gene contains 2 cytosine-guanine dinucleotide (CpG) islands, and the intragenic 3' CpG was entirely demethylated in SU-DHL-1 and DEL. In contrast to HD, in which NF-kappa B was constitutively activated, ALCL cells consistently showed (p50)(2) homodimer binding activity on electrophoretic mobility shift assay. It is suggested that the high-level nuclear Bcl-3 sequesters the (p50)(2) homodimer to the nucleus, which may account for the contradictory effect of CD30 stimulation on ALCL and HD. We propose that BCL3 is overexpressed by genetic and epigenetic modifications, potentially contributing to the development of t(2;5)(+) ALCL.
Nishikori
Momoko
M
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Japan.
Maesako
Yoshitomo
Y
Ueda
Chiyoko
C
Kurata
Masayuki
M
Uchiyama
Takashi
T
Ohno
Hitoshi
H
D000081242:B-Cell Lymphoma 3 Protein; D002889:Chromosomes, Human, Pair 2; D002895:Chromosomes, Human, Pair 5; D018899:CpG Islands; D003937:Diagnosis, Differential; D019281:Dimerization; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors