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AML

PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kB, MAPkinase and p53 pathways

Leukemia volume 19, pages 586–594 (2005)Cite this article

A Correction to this article was published on 15 October 2021

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Abstract

The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34+38− AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kB activity and promotes p53-mediated transcription. This is associated with a synergistic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara-C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.

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Acknowledgements

VL Grandage and A Khwaja were sponsored by the Kay Kendall Leukaemia Research Fund and Medical Research Council, respectively.

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  1. Department of Haematology, Royal Free and University College London Medical School, 98 Chenies Mews, London, UK

    V L Grandage, R E Gale, D C Linch & A Khwaja

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  1. V L Grandage
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  2. R E Gale
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  3. D C Linch
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  4. A Khwaja
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Correspondence to V L Grandage.

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Grandage, V., Gale, R., Linch, D. et al. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kB, MAPkinase and p53 pathways. Leukemia 19, 586–594 (2005). https://doi.org/10.1038/sj.leu.2403653

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