Selective Targeting of Leukemic Cell Growth in Vivo and in Vitro Using a Gene Silencing Approach to Diminish S-Adenosylmethionine Synthesis

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-II beta 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 mu M), 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-II beta ablation and the consequent reduction in SAMe synthesis. In our NOD/Scid IL-2R gamma(null) humanized mouse model of leukemia, control shRNA-transduced Jurkat cells exhibited heightened engraftment, whereas cells lacking MAT-II beta failed to engraft for up to 5 weeks post-transplant. These stark differences in malignant cell survival, effected by MAT-II beta 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.