A deletion in the gene for transforming growth factor beta type I receptorabolishes growth regulation by transforming growth factor beta in a cutaneous T-cell lymphoma

Spontaneous regression of skin lesions is characteristic of lymphomatoid pa pulosis (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 occur s. 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-polymeras e 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 t o the deletion was detected in the genomes of TGF-beta-responsive cells, bu t not in JK cells, indicating that they contain no wild-type T beta R-I gen e. PCR primers that flanked the deleted T beta R-I region amplified a singl e hand from JK cell genomic DNA that lacked the last 178 bp of exon 1 and a ll 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-res ponsive cells and was also readily detected in tumor biopsies obtained befo re the establishment of the JK cell line. Our results identify the first in activating 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 Soci ety of Hematology.