ArticleThe Journal of biological chemistry2008
Selective targeting of leukemic cell growth in vivo and in vitro using a gene silencing approach to diminish S-adenosylmethionine synthesis.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 22 citations in OpenAlex.
- Review
- SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with theMedComm · 2024Article
- Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A.Biochemistry · 2021Article
- Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A.Nature chemical biology · 2017Article
- Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Article
- Anti-leukemic response of a NSAID, tolfenamic acid.Targeted oncology · 2014Article
- Proteomic profile of pre - B2 lymphoblasts from children with acute lymphoblastic leukemia (ALL) in relation with the translocation (12; 21).Clinical proteomics · 2014Article
- S-adenosylmethionine limitation induces p38 mitogen-activated protein kinase and triggers cell cycle arrest in G1.Journal of cell science · 2014Article
- Targeted nanoparticles for pediatric leukemia therapy.Frontiers in oncology · 2014Review
- Neurodegeneration in multiple sclerosis involves multiple pathogenic mechanisms.Degenerative neurological and neuromuscular disease · 2014Review
- Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells.Cell cycle (Georgetown, Tex.) · 2012Article
- Efficient induction of extrinsic cell death by dandelion root extract in human chronic myelomonocytic leukemia (CMML) cells.PloS one · 2012Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
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