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
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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DOI：
10.1182/blood.v94.8.2854.420k07_2854_2861
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发表时间：
1999-10-15
期刊：
影响因子：
20.3
通讯作者：
Lodish, HF
中科院分区：
文献类型：
--
作者：
Schiemann, WP;Pfeifer, WM;Lodish, HF
皮肤病变的自然消退是淋巴瘤样丘疹病（LyP）的特征，LyP是一种克隆性皮肤淋巴组织增生性疾病。少数LyP患者进展为间变性大细胞淋巴瘤（ALCL），其中皮肤病变不再消退，并且经常发生皮外播散。在一个这样的情况下，我们开发了一种肿瘤细胞系，JK细胞，并表明，这些细胞是抵抗生长抑制作用的转化生长因子β（TGF-β）由于损失的细胞表面表达的TGF-β I型受体（T β R-I）。逆转录-聚合酶链反应（RI-PCR）和测序的JK细胞T β R-I cDNA克隆确定了一个缺失，跨越最后178 bp的外显子1，包括起始蛋氨酸。在TGF-β反应细胞的基因组中检测到缺失内部的放射性标记片段的杂交，但在JK细胞中未检测到，表明它们不含野生型T β R-I基因。位于缺失的T β R-I区域侧翼的PCR引物从JK细胞基因组DNA扩增出单手，所述JK细胞基因组DNA缺少外显子1的最后178 bp和全部约5 kb的内含子1。这种JK细胞特异性基因组T β R-I PCR产物与从TGF-β应答细胞扩增的产物不同，并且在建立JK细胞系之前获得的肿瘤活检中也容易检测到。我们的研究结果确定了人类淋巴瘤中T β R-I基因的第一个失活突变，使其对TGF-β的生长抑制不敏感。(C)1999年，美国血液学会。
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.