A deletion in the gene for transforming growth factor β type I receptor abolishes growth regulation by transforming growth factor β 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 (T beta R-I). Reverse transcriptase-polymerase chain reaction (RI-PCR) and sequencing of JK cell T beta R-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 T beta R-I gene. PCR primers that flanked the deleted T beta R-I region amplified a single hand from JK cell genomic DNA that lacked the last 178 bp of exon 1 and all of the approximate to 5 kb of intron 1. This JK cell-specific genomic T beta R-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 T beta R-I gene in a human lymphoma that renders it insensitive to growth inhibition by TGF-beta. (C) 1999 by The American Society of Hematology.