The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation

Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML a...

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Veröffentlicht in:Blood 2010-11, Vol.116 (20), p.4262-4273
Hauptverfasser: Green, Alexa S., Chapuis, Nicolas, Trovati Maciel, Thiago, Willems, Lise, Lambert, Mireille, Arnoult, Christophe, Boyer, Olivier, Bardet, Valerie, Park, Sophie, Foretz, Marc, Viollet, Benoit, Ifrah, Norbert, Dreyfus, François, Hermine, Olivier, Cruz Moura, Ivan, Lacombe, Catherine, Mayeux, Patrick, Bouscary, Didier, Tamburini, Jerome
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Sprache:eng
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Zusammenfassung:Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite dephosphorylation of the key translation regulator, 4E-BP1, which markedly inhibits the initiation step of mRNA translation. Consequently, metformin reduces the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong antileukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus represents a promising new strategy for AML therapy.
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2010-02-269837