title: Selective targeting of leukemic cell growth in vivo and in vitro using a gene silencing approach to diminish S-adenosylmethionine synthesis.
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.
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Ramy R
authors.initials: RR
authors.lastname: Attia
authors.forename: Lidia A
authors.initials: LA
authors.lastname: Gardner
authors.forename: Engy
authors.initials: E
authors.lastname: Mahrous
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Taxman
authors.forename: Leighton
authors.initials: L
authors.lastname: Legros
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowe
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.forename: Arthur
authors.initials: A
authors.lastname: Geller
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb