title: Antileukemic activity of rapamycin in acute myeloid leukemia.
abstract: The mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U563, CPTP, Département d'Oncogenèse et signalisation dans les cellules hématopoïétiques, IFR30, Toulouse, France. recher.c@chu-toulouse.fr
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.forename: Odile
authors.initials: O
authors.lastname: Beyne-Rauzy
authors.forename: Cécile
authors.initials: C
authors.lastname: Demur
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Chicanne
authors.forename: Cédric
authors.initials: C
authors.lastname: Dos Santos
authors.forename: Véronique Mansat-De
authors.initials: VM
authors.lastname: Mas
authors.forename: David
authors.initials: D
authors.lastname: Benzaquen
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.forename: Françoise
authors.initials: F
authors.lastname: Huguet
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012008:Recurrence; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus