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

The online version of this article has a Supplementary Appendix. BackgroundAlterations 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 MethodsWe 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. ResultsIn 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. ConclusionsOur 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.Citation: Chapuis N, Tamburini J, Gillot L, Bardet V, Willems L, Park S, Green AS, Ifrah N, Dreyfus F, Mayeux P, Lacombe C,ing is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti- IGF-1R antibody. Haematologica. 2010; 95:415-423. doi:10.3324/haematol.2009 This is an open-access paper.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

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

“…62 Using neutralizing anti IGF-1R antibodies (Ab), anti IGF-1 Ab or IGF-1 siRNA in primary blast cells, we have found that constitutive PI3K activation is due to an IGF-1/IGF-1R autocrine loop in 70% of cases. 78 Moreover, we report in this same study that the inhibition of AKT phosphorylation with neutralizing anti IGF-1R antibodies blocks the proliferation of blast cells and inhibits the clonogenicity of leukemic progenitors but does not induce significant apoptosis. 78 Other potential mechanisms of PI3K activation in AML might also implicate autocrine/paracrine VEGF or angiopoietin secretion.…”

“…78 Moreover, we report in this same study that the inhibition of AKT phosphorylation with neutralizing anti IGF-1R antibodies blocks the proliferation of blast cells and inhibits the clonogenicity of leukemic progenitors but does not induce significant apoptosis. 78 Other potential mechanisms of PI3K activation in AML might also implicate autocrine/paracrine VEGF or angiopoietin secretion. 79,80 Blast cells also directly interact with the bone marrow micro-environment, and ITA4 (VLA-4) / FINC (fibronectin) interactions activate PI3K in blast cells.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…140 In many AMLs, mTORC1 activation may be dependent on an autocrine insulin-like growth factor-1/insulin-like growth factor-1 receptor loop. 141,142 It is emerging that protein synthesis in some AMLs is resistant to rapamycin and that other targeting approaches should be developed. 140 Indeed, it has been shown that the 4E-BP1 protein was phosphorylated indirectly by events mediated by the Pim-2 (proviral integration Moloney murine leukemia virus) serine/threonine on S65, which contributed to the rapamycin resistance of the cells.…”

Expression and Clinical Significance of Insulin-Like Growth Factor 1 in Lung Cancer Tissues and Perioperative Circulation from Patients with Non-Small-Cell Lung Cancer

“…Ohlsson et al 17 suggested a revision in the classical somatomedin hypothesis and proposed the "dual somatomedin hypothesis" in which autocrine/ paracrine igf-1 is the main determinant of postnatal body growth, and liver-derived endocrine-acting igf-1 supplies negative feedback to gh secretion and possibly exerts other effects on carbohydrate and lipid metabolism. Paracrine/autocrine igf-1 promotes the growth of many cancers, such as acute myeloid leukemia 18 , chronic myelogenous leukemia 19 , neuroendocrine tumour 20 , breast cancer 21 , and cervical cancer 22 . Pulmonary neuroendocrine tumours such as carcinoids can produce ectopic gh in sufficient quantities to manifest as acromegaly, potentially contributing to local and distant igf activation loops 23 .…”