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J Biol Chem ; 283(45): 30788-95, 2008 Nov 07.
Article in English | MEDLINE | ID: mdl-18753136

ABSTRACT

We exploited the fact that leukemic cells utilize significantly higher levels of S-adenosylmethionine (SAMe) than normal lymphocytes and developed tools that selectively diminished their survival under physiologic conditions. Using RNA interference gene silencing technology, we modulated the kinetics of methionine adenosyltransferase-II (MAT-II), which catalyzes SAMe synthesis from ATP and l-Met. Specifically, we silenced the expression of the regulatory MAT-IIbeta subunit in Jurkat cells and accordingly shifted the K(m L-Met) of the enzyme 10-15-fold above the physiologic levels of l-Met, thereby reducing enzyme activity and SAMe pools, inducing excessive apoptosis and diminishing leukemic cell growth in vitro and in vivo. These effects were reversed at unphysiologically high l-Met (>50 microm), indicating that diminished leukemic cell growth at physiologic l-Met levels was a direct result of the increase in MAT-II K(m L-Met) due to MAT-IIbeta ablation and the consequent reduction in SAMe synthesis. In our NOD/Scid IL-2Rgamma(null) humanized mouse model of leukemia, control shRNA-transduced Jurkat cells exhibited heightened engraftment, whereas cells lacking MAT-IIbeta failed to engraft for up to 5 weeks post-transplant. These stark differences in malignant cell survival, effected by MAT-IIbeta ablation, suggest that it may be possible to use this approach to disadvantage leukemic cell survival in vivo with little to no harm to normal cells.


Subject(s)
Apoptosis , Gene Expression Regulation, Leukemic , Gene Expression Regulation , Leukemia/enzymology , Methionine Adenosyltransferase/biosynthesis , RNA Interference , Adenosine Triphosphate/genetics , Adenosine Triphosphate/metabolism , Animals , Apoptosis/genetics , Cell Survival/genetics , Disease Models, Animal , Gene Expression Regulation/genetics , Gene Expression Regulation, Leukemic/genetics , Humans , Jurkat Cells , Leukemia/genetics , Leukemia/therapy , Methionine/genetics , Methionine/metabolism , Methionine Adenosyltransferase/genetics , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , S-Adenosylmethionine/biosynthesis , S-Adenosylmethionine/genetics
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