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Originally published online as doi:10.1189/jlb.0608383 on November 12, 2008

Published online before print November 12, 2008
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(Journal of Leukocyte Biology. 2009;85:165-174.)
© 2009 by Society for Leukocyte Biology

Mechanisms of SHP-1 P2 promoter regulation in hematopoietic cells and its silencing in HTLV-1-transformed T cells

Koichi Nakase, Jihua Cheng, Quan Zhu and Wayne A. Marasco1

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

1 Correspondence: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115, USA. E-mail: wayne_marasco{at}dfci.harvard.edu

The Src homology-2-containing protein-tyrosine phosphatase 1 (SHP-1), is a negative regulator of cell signaling. It is also considered a tumor suppressor gene because of its ability to antagonize the action of tyrosine kinases. Although SHP-1 is expressed strongly in hematopoietic cells, decreased expression has been observed in various hematological malignancies, which suggests a central involvement of SHP-1 in leukemogenesis. We have shown previously that human T cell lymphotropic virus type-1 (HTLV-1) Tax-induced promoter silencing (TIPS) is an early event causing down-regulation of SHP-1 expression, which is dependent on NF-{kappa}B. In this study, DNase I footprinting and EMSA also revealed binding of transcription factors, specificity protein 1 (Sp1) and octamer-binding transcription factor 1 (Oct-1) to the P2 promoter, and site-directed mutagenesis confirmed that these factors contribute to the basal P2 promoter activity. Chromatin immunoprecipitation (CHIP) assays showed that Sp1, Oct-1, NF-{kappa}B, CREB-1, and RNA polymerase II interacted with the core SHP-1 P2 promoter in CD4+ T cells and Jurkat cells but not in HTLV-1-transformed MT-2 and HUT102 cells when HTLV-1 Tax is present. Furthermore, bisulfite sequencing of the SHP-1 P2 core region revealed heavy CpG methylation in HTLV-1-transformed cells compared with freshly isolated CD4+ T cells and HTLV-1-noninfected T cell lines. A significant inverse correlation between degree of CpG methylation and expression of SHP-1 mRNA or protein was observed. Taken together, our data support the notion that in HTLV-1-transformed CD4+ T cells, TIPS causes dissociation of transcription factors from the core SHP-1 P2 promoter, which in turn leads to subsequent DNA methylation, an important early step for leukemogenesis.

Key Words: DNA methylation • adult T cell leukemia • leukemogenesis