transforming-growth-factor-beta and Lymphoma--Large-Cell--Anaplastic

Lymphomatoid papulosis and cutaneous CD30+ lymphoma are closely related conditions in which large atypical lymphocytes that have similar immunophenotypic features occur. In lymphomatoid papulosis, the lesions are papules and nodules that spontaneously involute. There are two polar histologic patterns, type A and B, in which the large atypical cells resemble those of Hodgkin's disease and mycosis fungoides, respectively, but in many cases, features of both types are present, either separately or in the same lesions. Variants of lymphomatoid papulosis include cases with a perifollicular distribution and those with lymphocytic vasculitis or dermal mucin deposits. Clinical lesions that tend to be stable, a monomorphous cellular composition, and in the case of immunocompromised patients, the presence of Epstein-Barr viral genome characterize cutaneous CD30+ lymphoma. A loss of response to transforming growth factor-beta, which normally dampens cellular proliferation, may differentiate CD30+ lymphoma from lymphomatoid papulosis.

Topics: Cell Division; Genome, Viral; Hair Follicle; Herpesvirus 4, Human; Hodgkin Disease; Humans; Immunocompromised Host; Immunophenotyping; Lymphocytes; Lymphoma, Large-Cell, Anaplastic; Lymphomatoid Papulosis; Mucins; Mycosis Fungoides; Skin Neoplasms; Transforming Growth Factor beta; Vasculitis, Leukocytoclastic, Cutaneous

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.

Topics: Activin Receptors, Type I; Animals; Blotting, Southern; Cell Division; Disease Progression; DNA Mutational Analysis; DNA, Complementary; DNA, Neoplasm; Exons; Humans; Introns; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell, Cutaneous; Lymphomatoid Papulosis; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Proteins; Neoplasm Transplantation; Protein Serine-Threonine Kinases; Receptor Protein-Tyrosine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; Sequence Deletion; Skin Neoplasms; Transforming Growth Factor beta; Transplantation, Heterologous