Abstract
The positive regulatory domain I (PRDM1) is a master regulator of terminal B-cell differentiation. However, PRDM1 is not B-cell specific. To determine its role in T-cell lymphoma, PRDM1 expression was investigated in 60 patients. PRDM1alpha and PRDM1beta transcripts were detected in laser-microdissected T-lymphoma cells in 27 and 14 patients, respectively, mostly in cases with IRF4 expression. PRDM1beta was associated with increased c-MYC expression. PRDM1beta-positive patients displayed advanced Ann Arbor stage and high-risk International Prognostic Index and were linked to short survival times. In vitro, PRDM1beta was related to resistance to chemotherapeutic agents and could be down-regulated by the proteasome inhibitor bortezomib. Kinetic studies showed that bortezomib down-regulation of PRDM1beta preceded decreased IRF4 and c-MYC expression. An earlier retaining of cytoplasmic IkappaBalpha in bortezomib-treated cells was revealed, concomitant with blockade of NF-kappaB nuclear translocation. These results demonstrate the involvement of PRDM1beta in T-cell lymphoma, with possible therapeutic interference by the proteasome inhibitor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Boronic Acids / pharmacology*
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Boronic Acids / therapeutic use
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Bortezomib
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Down-Regulation / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Leukemic / drug effects*
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Humans
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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Interferon Regulatory Factors / biosynthesis
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Interferon Regulatory Factors / genetics
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / metabolism*
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Lymphoma, T-Cell / mortality
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Lymphoma, T-Cell / pathology
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Microdissection
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NF-KappaB Inhibitor alpha
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Neoplasm Staging
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Positive Regulatory Domain I-Binding Factor 1
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Protease Inhibitors / pharmacology*
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Protease Inhibitors / therapeutic use
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors*
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Proto-Oncogene Proteins c-myc / biosynthesis
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Proto-Oncogene Proteins c-myc / genetics
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Pyrazines / pharmacology*
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Pyrazines / therapeutic use
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Repressor Proteins / biosynthesis*
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Repressor Proteins / genetics
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Survival Rate
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
Substances
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Boronic Acids
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I-kappa B Proteins
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Interferon Regulatory Factors
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MYC protein, human
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NFKBIA protein, human
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Protease Inhibitors
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Proteasome Inhibitors
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Proto-Oncogene Proteins c-myc
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Pyrazines
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Repressor Proteins
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Transcription Factors
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interferon regulatory factor-4
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PRDM1 protein, human
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NF-KappaB Inhibitor alpha
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Bortezomib
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Positive Regulatory Domain I-Binding Factor 1
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Proteasome Endopeptidase Complex