期刊
LEUKEMIA
卷 23, 期 6, 页码 1029-1038出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2008.395
关键词
acute myeloid leukaemia; PI3K/Akt pathway; phosphorylation; Akt inhibitor; therapeutic target; complex karyotype
资金
- La Ligue Nationale Contre le Cancer
- Association pour la Recherche sur le Cancer [4937]
- Association Cent Pour Sang La Vie!
- Institut National du Cancer
- Region Midi-Pyrenees
The phosphoinositide 3-kinase/Akt pathway is an important signalling pathway governing cell survival and proliferation in acute myeloid leukaemia (AML). As full activation of Akt requires phosphorylation on both threonine 308 (Thr308) and serine 473 (Ser473) residues, we studied the level of phosphorylation on the both sites in 58 AML samples by flow cytometry. The ratio of the mean fluorescence intensity of Thr308 and Ser473 represented a continuum ranging from 0.3 to 5.6 and from 0.4 to 2.87, respectively. There were no significant correlations between age, gender, French-American-British classification, leukocytosis, FLT3-ITD and Akt phosphorylation. However, the level of phosphorylation on Thr308, but not on Ser473, was significantly correlated with high-risk karyotype. Thr308(high) patients had significantly shorter overall survival (11 vs 47 months; P = 0.01), event-free survival (9 vs 26 months; P = 0.005) and relapse-free survival (10 months vs not reached; P = 0.02) than Thr308(low) patients. Neither screening for AKT1 E17K mutation nor changes in the level of PTEN expression and phosphorylation could be linked to increased phosphorylation on Thr308 in high-risk cytogenetic AML cells. However, PP2A activity was significantly reduced in high-risk samples compared with intermediate-risk samples. Moreover, the specific Akt inhibitor, Akti-1/2, inhibited cell proliferation and clonogenic properties, and induced apoptosis in AML cells with high-risk cytogenetics, suggesting that Akt may represent a therapeutic target in high-risk AML. Leukemia (2009) 23, 1029-1038; doi: 10.1038/leu.2008.395; published online 22 January 2009
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