Abstract
Transforming growth factor-β-stimulated clone-22 (TSC-22) is a gene that has been shown to be silenced in brain and prostate cancer, but its function and the mechanism responsible for this silencing are unknown. We used our model of spontaneous T-natural killer (NK) acute lymphoblastic leukemia (ALL) and discovered that the TSC-22 promoter was methylated resulting in absent expression in seven of eight cases of primary NK-T ALL, but not in cells from normal mice or mice with polyclonal expansion of T and NK cells. We found that TSC-22 was undetectable or minimally expressed in mouse lymphoma cell lines YAC-1 and EL-4 and human leukemia cell lines Jurkat and RPMI 8866, but treatment with the demethylation agent 5-aza-2′-deoxycytidine restored or increased TSC-22 expression. We mapped the TSC-22 promoter and discovered a CPG island in the proximal region and determined that its methylation was responsible for the decreased gene expression. Over-expression of TSC-22 slowed in vitro cell growth and resulted in a dramatic decrease of tumor size in vivo. Finally, TSC-22 expression was found to be absent or substantially reduced in human chronic lymphocytic leukemia and acute myeloid leukemia compared to normal human tissue. Collectively, our data indicate that TSC-22 is silenced via DNA methylation within its proximal promoter, and this silencing appears to contribute to its function as a putative tumor suppressor gene in leukemia. Silencing of TSC-22 can be reversed by 5-aza-2′-deoxycytidine, recently approved by the FDA for the treatment of myelodysplastic syndrome.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.