A deletion in the gene for transforming growth factor beta type I receptor abolishes growth regulation by transforming growth factor beta in a cutaneous T-cell lymphoma.
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.
Schiemann
W P
WP
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridgge, MA 02142, USA.
Pfeifer
W M
WM
Levi
E
E
Kadin
M E
ME
Lodish
H F
HF
D030201:Activin Receptors, Type I; D000818:Animals; D015139:Blotting, Southern; D002455:Cell Division; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000473:pathology; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000473:pathology; D017731:Lymphomatoid Papulosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I