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2.
J Invest Dermatol ; 115(6): 1034-40, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11121138

ABSTRACT

Lymphomatoid papulosis is part of a spectrum of CD30+ cutaneous lymphoproliferative disorders characterized by spontaneous tumor regression. The mechanism(s) of regression is unknown. In a recent study, a selective increase in CD30 ligand expression in regressing lesions of lymphomatoid papulosis and cutaneous CD30+ anaplastic large cell lymphoma was shown, suggesting that activation of the CD30 signaling pathway may be responsible for tumor regression, whereas no difference in Fas/Fas ligand expression was found between regressing and nonregressing lesions. Therefore we tested the effects of CD30 and Fas activation on three CD30+ cutaneous lymphoma cell lines (Mac-1, Mac-2 A, JK) derived from nonregressing tumors of two patients who had progressed from lymphomatoid papulosis to systemic anaplastic large cell lymphoma. To evaluate the effects of CD30 signaling, the cell lines were incubated with a CD30 agonistic antibody, HeFi-1. Proliferative responses, mitogen-activated protein kinase, and nuclear factor kappa B activities were determined with and without CD30 activation. Mac-1 and Mac-2 A showed increased proliferative responses to incubation with CD30 activating antibody, HeFi-1. Inhibition of the mitogen-activated protein kinase activity caused growth inhibition of the Mac-1, Mac-2 A, and JK cell lines. Activation of the Fas pathway induced apoptosis in all three cell lines. Taken together, these findings suggest that resistance to CD30-mediated growth inhibition provides a possible mechanism for escape of cutaneous anaplastic large cell lymphoma from tumor regression. Mitogen-activated protein kinase inhibitors are potential therapeutic agents for the treatment of advanced cutaneous anaplastic large cell lymphoma. J Invest Dermatol 115:1034-1040, 2000


Subject(s)
Ki-1 Antigen/physiology , Lymphoma/pathology , Skin Neoplasms/pathology , fas Receptor/physiology , Cell Division/immunology , Disease Progression , Humans , Immunohistochemistry , Mitogen-Activated Protein Kinases/physiology , NF-kappa B/physiology , Signal Transduction , Tumor Cells, Cultured
3.
Blood ; 94(8): 2854-61, 1999 Oct 15.
Article in English | MEDLINE | ID: mdl-10515889

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 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.


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