Published online 30 November 2009
Haematologica, Vol 95, Issue 5, 819-828 doi:10.3324/haematol.2009.013797
Copyright © 2010 by Ferrata Storti Foundation
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Park, S.
Right arrow Articles by Bouscary, D.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Park, S.
Right arrow Articles by Bouscary, D.

Acute Myeloid Leukemia

Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia

Sophie Park1,2,3,5,7, Nicolas Chapuis1,2,3,4, Jérôme Tamburini1,2,3,5,7, Valérie Bardet1,2,3,4, Pascale Cornillet-Lefebvre6,7, Lise Willems1,2,3, Alexa Green1,2,3, Patrick Mayeux1,2,3, Catherine Lacombe1,2,3,4,7, Didier Bouscary1,2,3,5,7

1 Institut Cochin, Département d’Hématologie, CNRS, UMR8104, Paris
2 INSERM, U567, Paris, France
3 Université Paris Descartes, Faculté de Médecine René Descartes, Paris
4 Service d’Hématologie Biologique, Hôpital Cochin, AP-HP, Paris
5 Service de Médecine Interne - UF d’Hématologie, Hôpital Cochin, AP-HP, Paris
6 Laboratoire d’hématologie, Centre Hospitalier-Universitaire (CHU) Reims
7 Groupe Ouest Est des Leucémies et Autres Maladies du Sang (GOELAMS), France

Correspondence: Didier Bouscary, Département d’Immunologie-Hématologie, Equipe 35, Hôpital. Cochin, 27, rue du Faubourg Saint-Jacques F-75014 Paris, France. E-mail: didier.bouscary{at}inserm.fr/didier.bouscary{at}cch.aphp.fr

The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110{delta} isoform of class IA PI3K. Constitutive PI3K activation is the result of autocrine IGF-1/IGF-1R signaling in 70% of acute myeloid leukemia samples but specific inhibition of this pathway does not induce apoptosis. Specific inhibition of PI3K/AKT or mTORC1 alone in vitro has anti-leukemic effects which are essentially exerted via the suppression of proliferation. However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells. Moreover, mTORC1 inhibition using sirolimus overactivates PI3K/AKT via the upregulation of IRS2 expression and by favoring IGF-1/IGF-1R autocrine signaling. Recent data also indicate that mTORC1 does not control protein translation in acute myeloid leukemia. These results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).




This article has been cited by other articles:


Home page
 haematolHome page
J. Peccatori and F. Ciceri
Allogeneic stem cell transplantation for acute myeloid leukemia
Haematologica, June 1, 2010; 95(6): 857 - 859.
[Full Text] [PDF]