title: 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.
abstract: 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.
  
  
  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.
authors.affiliation: Département d'Hématologie, Institut Cochin, CNRS, UMR8104, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.forename: Jérôme
authors.initials: J
authors.lastname: Tamburini
authors.forename: Pascale
authors.initials: P
authors.lastname: Cornillet-Lefebvre
authors.forename: Lucile
authors.initials: L
authors.lastname: Gillot
authors.forename: Valérie
authors.initials: V
authors.lastname: Bardet
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Green
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D017209:Apoptosis; D019898:Autocrine Communication; D001752:Blast Crisis; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000628:therapy; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D057134:Antibodies, Neutralizing; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt