ABSTRACT
Post-transplant lymphoproliferative disorder (PTLD) is a frequent and often fatal complication of organ transplantation. It most often results from an Epstein-Barr virus (EBV)-transformed B-cell clone, which expresses B-cell surface markers such as CD20. We describe a case of a heart transplant recipient who EBV seroconverted post-transplant and subsequently developed subcutaneous and lymphatic B-cell lymphoma, successfully treated with CD20 antibody (rituximab). The patient has been in remission during 10 months of clinical follow-up.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Epstein-Barr Virus Infections/etiology , Heart Transplantation/adverse effects , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/etiology , Antibodies, Monoclonal, Murine-Derived , Antigens, CD20/analysis , Biomarkers, Tumor/analysis , Child , Epstein-Barr Virus Infections/blood , Epstein-Barr Virus Infections/drug therapy , Humans , Immunosuppression Therapy/adverse effects , Lymphoproliferative Disorders/diagnosis , Male , RituximabABSTRACT
Expression of the rat gene designated S14 is rapidly and markedly induced by 3,3',5-triiodo-L-thyronine (T3) in the liver. We have used nuclear run-on assays and transfection studies to explore the basis of this regulation. These studies indicate that T3 induction of hepatic S14 mRNA is due primarily, if not exclusively, to changes in the rate of gene transcription. Both alpha and beta forms of the thyroid hormone receptor (c-erbA) can activate S14 promoter activity in a co-transfection assay. This activation occurs in a dose-dependent manner and requires the expression of the T3 receptor from transfected cDNA in either COS-1 cells or primary rat hepatocytes. Delineation of sequences essential for control of S14 promoter activity indicates that multiple thyroid hormone response elements (TREs) are involved. These TREs have been localized in the far upstream 5'-flanking region of the S14 gene, approximately 2.7 kilobases from the S14 transcriptional initiation site. DNA-binding studies with in vitro translated c-erbA indicate that each of the S14 TREs contains a specific binding site for the receptor. The location of the S14 TREs far upstream from the promoter site may necessitate the presence of multiple TREs for hormonal responsiveness.
Subject(s)
DNA/metabolism , Gene Expression/drug effects , Promoter Regions, Genetic , Receptors, Thyroid Hormone/metabolism , Triiodothyronine/pharmacology , Animals , Base Sequence , Binding Sites , Chloramphenicol O-Acetyltransferase , Cloning, Molecular , DNA, Recombinant , Kinetics , Male , Molecular Sequence Data , Nucleic Acid Hybridization , Proto-Oncogene Proteins/genetics , RNA, Messenger/biosynthesis , Rats , Rats, Inbred Strains , Restriction Mapping , Transcription, Genetic/drug effects , TransfectionABSTRACT
The DNA sequences involved in control of S14 gene expression in response to carbohydrate have been studied. The levels of S14 mRNA in primary hepatocytes increase when glucose in the media is elevated from 5.5 to 27.7 mM in the presence of insulin. Following lipofection of primary hepatocytes, plasmids containing S14 genomic sequences from -4316 to +19 relative to the start of transcription were sufficient to confer glucose regulation to the linked marker gene, chloramphenicol acetyltransferase. Deletions of the S14 sequences between -4316 and -1601 led to a significant reduction in glucose-stimulated activity with each successive deletion, suggesting the presence of multiple regulatory elements. The response of the transfected construct containing 4316 base pairs of S14 5'-flanking region mimicked changes in the endogenous S14 mRNA levels in all hormonal and nutritional conditions tested, supporting the physiological significance of the response.
Subject(s)
Genes , Glucose/pharmacology , Liver/metabolism , Promoter Regions, Genetic , RNA, Messenger/genetics , Animals , Cells, Cultured , Chromosome Deletion , Gene Expression Regulation/drug effects , Genetic Vectors , Male , Plasmids , RNA, Messenger/drug effects , Rats , Rats, Inbred F344 , Restriction Mapping , Transcription, Genetic/drug effects , TransfectionABSTRACT
Two distinct v-erbA-related cDNA clones representing the products of different genes were isolated from a rat liver cDNA library. The first, rc-erbA-alpha, was 82% identical to v-erbA and encoded a polypeptide with a calculated molecular mass of 45,000 daltons. This cDNA clone arises from the same gene product as a v-erbA-related cDNA isolated from rat brain by Thompson et al. (Thompson, C. C., Weinberger, C., Lebo, R., and Evans, R. (1987) Science 237, 1610-1614). The second cDNA clone, rc-erbA-beta, was 76% identical to v-erbA and encoded a polypeptide with a calculated molecular mass of 52,000 daltons. Both rc-erbA-alpha and rc-erbA-beta translational products bound 3,5,3'-triiodo-L-thyronine with affinities equal to each other (Kd approximately equal to 0.4 nM) and comparable to the nuclear thyroid hormone receptor extracted from rat liver. The relative affinities of a series of thyroid hormone analogs for both translational products were also identical. In various tissues and cell lines, the relative levels of rc-erbA-beta RNA, but not rc-erbA-alpha RNA, correlated with measurements of nuclear 3,5,3'-triiodo-L-thyronine binding sites. Based on this correlation, we suggest that rc-erbA-beta may encode the "classical" nuclear thyroid hormone receptor, whereas rc-erbA-alpha may encode an isoreceptor species with differing functional properties.
