Antileukemic activity of rapamycin in acute myeloid leukemia.
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.
Récher
Christian
C
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
Beyne-Rauzy
Odile
O
Demur
Cécile
C
Chicanne
Gaëtan
G
Dos Santos
Cédric
C
Mas
Véronique Mansat-De
VM
Benzaquen
David
D
Laurent
Guy
G
Huguet
Françoise
F
Payrastre
Bernard
B
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
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