Abstract
Spontaneous regression of skin lesions is characteristic of lymphomatoid papulosis (LyP), a clonal cutaneous lymphoproliferative disorder. A minority of LyP patients progress to anaplastic large cell lymphoma (ALCL) in which skin lesions no longer regress and extracutaneous dissemination often occurs. In 1 such case, we developed a tumor cell line, JK cells, and show that these cells are resistant to the growth inhibitory effects of transforming growth factor beta (TGF-beta) due to the loss of cell surface expression of the TGF-beta type I receptor (TbetaR-I). Reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing of JK cell TbetaR-I cDNA clones identified a deletion that spanned the last 178 bp of exon 1, including the initiating methionine. Hybridization of a radiolabeled fragment internal to the deletion was detected in the genomes of TGF-beta-responsive cells, but not in JK cells, indicating that they contain no wild-type TbetaR-I gene. PCR primers that flanked the deleted TbetaR-I region amplified a single band from JK cell genomic DNA that lacked the last 178 bp of exon 1 and all of the approximately 5 kb of intron 1. This JK cell-specific genomic TbetaR-I PCR product was distinct from products amplified from TGF-beta-responsive cells and was also readily detected in tumor biopsies obtained before the establishment of the JK cell line. Our results identify the first inactivating mutation in TbetaR-I gene in a human lymphoma that renders it insensitive to growth inhibition by TGF-beta.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activin Receptors, Type I*
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Animals
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Blotting, Southern
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Cell Division
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DNA Mutational Analysis
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DNA, Complementary / genetics
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DNA, Neoplasm / genetics*
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Disease Progression
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Exons / genetics
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Humans
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Introns / genetics
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Lymphoma, Large-Cell, Anaplastic / genetics*
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Lymphoma, Large-Cell, Anaplastic / pathology
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Lymphoma, T-Cell, Cutaneous / genetics*
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Lymphoma, T-Cell, Cutaneous / pathology
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Lymphomatoid Papulosis / genetics*
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Lymphomatoid Papulosis / pathology
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Middle Aged
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / physiology
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Neoplasm Transplantation
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / physiology
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Receptor Protein-Tyrosine Kinases / deficiency
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / physiology
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / deficiency
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Receptors, Transforming Growth Factor beta / genetics*
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Receptors, Transforming Growth Factor beta / physiology
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Deletion*
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Transforming Growth Factor beta / pharmacology*
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Transplantation, Heterologous
Substances
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DNA, Complementary
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DNA, Neoplasm
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Neoplasm Proteins
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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Receptor Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I