Published online 8 December 2009
Haematologica, Vol 95, Issue 3, 415-423 doi:10.3324/haematol.2009.010785
Copyright © 2010 by Ferrata Storti Foundation
Nicolas Chapuis1,2,3,4 ,
Jérôme Tamburini1,2,3,5,8 ,
Pascale Cornillet-Lefebvre6,8 ,
Lucile Gillot6 ,
Valérie Bardet1,2,3,4 ,
Lise Willems1,2,3 ,
Sophie Park1,2,3,5,8 ,
Alexa S Green1,2,3 ,
Norbert Ifrah7,8 ,
François Dreyfus1,2,3,5,8 ,
Patrick Mayeux1,2,3 ,
Catherine Lacombe1,2,3,4,8 ,
Didier Bouscary1,2,3,5,8
Haematologica, Vol 95, Issue 3, 415-423 doi:10.3324/haematol.2009.010785
Copyright © 2010 by Ferrata Storti Foundation
Acute Myeloid Leukemia |
Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody
1 Institut Cochin, Département d’Hématologie, CNRS, UMR8104, Paris, France;
2 INSERM, U567, Paris, France;
3 Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France;
4 Service d’Hématologie Biologique, Hôpital Cochin, AP-HP, Paris, France;
5 Service de Médecine Interne-UF d’Hématologie, Hôpital Cochin, AP-HP, Paris, France;
6 Laboratoire d’hématologie, Centre Hospitalo-Universitaire (CHU) Reims, France;
7 Service des Maladies du Sang, CHU Angers, France and
8 Groupe Ouest Est des Leucémies et Autres Maladies du Sang (GOELAMS), France
Correspondence: Didier Bouscary, Département d’Hématologie, Institut Cochin, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail: didier.bouscary{at}inserm.fr/didier.bouscary{at}cch.aphp.fr
Background: Alterations in the PI3K/Akt pathway are found in a wide range of cancers and the development of PI3K inhibitors represents a promising approach to cancer therapy. Constitutive PI3K activation, reflecting an intrinsic oncogenic deregulation of primary blast cells, is detected in 50% of patients with acute myeloid leukemia. However, the mechanisms leading to this activation are currently unknown. As we previously reported IGF-1 autocriny in acute myeloid leukemia cells, we investigated whether IGF-1 signaling was involved in the constitutive activation of PI3K.
Design and Methods: We analyzed the IGF-1/IGF-1R signaling pathway and PI3K activity in 40 acute myeloid leukemia bone marrow samples. Specific inhibition of IGF-1/IGF-1R signaling was investigated using neutralizing anti-IGF-1R, anti-IGF-1 antibodies or IGF-1 short interfering RNA. The anti-leukemic activity of the neutralizing anti-IGF-1R was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation and survival.
Results: In all samples tested, we found that functional IGF-1R was constantly expressed in leukemic cells. In the acute myeloid leukemia samples with PI3K activation, we found that the IGF-1R was constitutively phosphorylated, although no IGF-1R activating mutation was detected. Specific inhibition of IGF-1R signaling with neutralizing anti-IGF-1R strongly inhibited the constitutive phosphorylation of both IGF-1R and Akt in 70% of the PI3K activated samples. Moreover, both incubation with anti-IGF-1 antibody and IGF-1 short interfering RNA inhibited Akt phosphorylation in leukemic cells. Finally, neutralizing anti-IGF-1R treatment decreased the clonogenicity of leukemic progenitors and the proliferation of PI3K activated acute myeloid leukemia cells.
Conclusions: Our current data indicate a critical role for IGF-1 autocriny in constitutive PI3K/Akt activation in primary acute myeloid leukemia cells and provide a strong rationale for targeting IGF-1R as a potential new therapy for this disease.
Key words: acute myeloid leukemia, class IA PI3Kinase, IGF-1 autocriny, targeted therapy.
This article has been cited by other articles:
 |
|
 |
|
  S. Park, N. Chapuis, J. Tamburini, V. Bardet, P. Cornillet-Lefebvre, L. Willems, A. Green, P. Mayeux, C. Lacombe, and D. Bouscary Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia Haematologica, May 1, 2010; 95(5): 819 - 828. [Abstract] [Full Text] [PDF]
|
|