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 Blood, 15 June 2007, Vol. 109, No. 12, pp. 5301-5307.
Prepublished online as a Blood First Edition Paper on March 5, 2007; DOI 10.1182/blood-2006-06-032128.

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IMMUNOBIOLOGY

Resistance to TGF-ß1 correlates with aberrant expression of TGF-ß receptor II in human B-cell lymphoma cell lines

Gang Chen1, Paritosh Ghosh1, Hiroshi Osawa1, Carl Y. Sasaki1, Louis Rezanka1, Jiandong Yang2, Thomas J. O'Farrell1, and Dan L. Longo1

1 Lymphocyte Cell Biology Unit, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD; 2 Laboratory of Genetics, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore

Resistance to transforming growth factor (TGF)–ß1–mediated growth suppression in tumor cells is often associated with the functional loss of TGF-ß receptors. Here we describe two B-cell lymphoma cell lines (DB and RL) that differ in their sensitivity to TGF-ß1–mediated growth suppression. The TGF-ß1–resistant cell line DB lacked functional TGF-ß receptor II (TßRII) in contrast to the TGF-ß–responsive cell line RL, whereas both cell lines had comparable levels of receptor I (TßRI). Lack of functional TßRII was correlated with the lack of TGF-ß1–induced nuclear translocation of phospho-Smad3 and phospho-Smad2, the lack of nuclear expression of p21Cip1/WAF1, and the down-regulation of c-Myc in DB cells. Transfection of wild-type, but not a C-terminal–truncated, form of TßRII rendered the DB cell line responsive to TGF-ß1–mediated growth suppression. Analysis of the TßRII gene in DB cells revealed the absence of TßRII message, which was reversed upon 5'-azacytidine treatment, indicating that the promoter methylation might be the cause of gene silencing. Promoter analysis revealed CpG methylations at –25 and –140 that correlated with the gene silencing. These data suggest that promoter methylation plays an important role in TßRII gene silencing and subsequent development of a TGF-ß1–resistant phenotype by some B-cell lymphoma cells.


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