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

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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 β (TGF-β) due to the loss of cell surface expression of the TGF-β type I receptor (TβR-I). Reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing of JK cell TβR-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-β–responsive cells, but not in JK cells, indicating that they contain no wild-type TβR-I gene. PCR primers that flanked the deleted TβR-I region amplified a single band from JK cell genomic DNA that lacked the last 178 bp of exon 1 and all of the ≈ 5 kb of intron 1. This JK cell-specific genomic TβR-I PCR product was distinct from products amplified from TGF-β–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 TβR-I gene in a human lymphoma that renders it insensitive to growth inhibition by TGF-β.