Table 3. Summary of mechanistic roles of IGF-IR in the pathogenesis of hematological malignancies.
| Disease Type | Major Pathways Involved | Mechanistic Role of IGF-IR | Outcome |
|---|---|---|---|
| PCM | PI3K/AKT: inhibition of apoptosis through the inhibition of cytochrome C release from mitochondria MAPK: induction of cellular proliferation PI3K/AKT/MAPK crosstalk: PI3K can directly phosphorylate MEK1/2 and MAPK |
IGF-I independent mechanism: direct phosphorylation of IRS molecules on IGF-IR, mainly IRS-2 IGF-I/IL-6 dual autocrine/paracrine loops contribute to PCM cells growth and survival through IGF-IR IGF-I dependent mechanism: IGF-I binding to IGF-IR, causing autophosphorylation of tyrosine residues and initiating downstream pathways IGF-II induced protection from apoptosis IGF-I induced inhibition of PTEN |
Effects on apoptosis and cellular proliferation |
| mTOR-dependent serine phosphorylation of IRS-1 enhances IGF-IR signaling and PI3K/AKT activation | IGF-I as a chemoattractant increases adhesion of PCM cells to fibronectin when PI3K/AKT is activated IGF-I induced association of IGF-IR and beta-1 integrin through the phosphorylation of IGF-IR, IRS-1, and PI3K IGF-I induced polymerization of F-actin, phosphorylation of FAK protein and paxillin, and enhance beta-1 integrin with focal adhesion proteins during homing process IGF-I increases migration of PCM cells in an AKT-dependent or -independent manner (such as PI3K-PKD or PI3K-RhoA pathways) |
Effects on adhesion, invasion, and migration | |
| Leukemia | PI3K/AKT and mTOR pathways are activated in immature AML cells Constitutive activation of AKT/PKB in AML blasts due to autocrine IGF-I/IGF-IR signaling |
IGF-I induced drug resistance in AML Inhibition of apoptosis |
Effects in AML |
| Pathway crosstalk: overactivation of PI3K/AKT via the upregulation of IRS-2 and IGF-IR autocrine signaling or through mTOR inhibition IGF-IR induced activation of JAK/STAT pathway IGF-IR induced upregulation of BCL-2, BCL-XL and inhibition of caspase activation |
Induction of cellular proliferation through deregulation of cell cycle molecules such as cyclin B1, cyclin E, and pCdc2 c-myb induced overexpression of IGF-I, IGF-II, and IGF-IR and a decrease in IGFBP-3 |
Effects in CML | |
| c-myb induced IGF-IR activation and downstream AKT and ERK pathways | |||
| Upregulation of IGF-IR and BCL-2 | Increased local production of serum IGF-I, independently of GH, controls autocrine/paracrine stimulation of IGF-IR | Effects in CLL | |
| IGF-IR impairs JNK, SHC, MAPK in B-ALL Y1250F/Y1251F mutant cells; IGF-I stimulation induced phosphorylation of AKT in the mutant cells, suggesting the Y1250F/Y1251F mutations can only hinder JNK, SHC, and MAPK pathways IGF-IR inhibition decreases PI3K/AKT, MAPK pathways while decreasing BCL-2 and BCL-XLand increases cleaved caspase 3 and PARP |
IGF-IR is preferentially expressed in T-ALL cell lines MicroRNA-223 decreases IGF-IR expression in T-ALL MicroRNA-99a and microRNA-100 overexpression inhibits the expression of IGF-IR and mTOR, as well as downstream proteins MCL-1 and FKBP51 in T-ALL |
Effects in T-ALL Effects in B-ALL |
|
| MDS | IGF-IR induced transformation of MDS to AML IGF-IR induced protection of apoptosis due to overexpression in advanced MDS subtypes |
Effects in MDS | |
| Lymphoma | IGF-IR induced activation of PI3K/AKT and JAK/STAT pathways | Novel functional interactions between IGF-IR and NPM-ALK in NPM-ALK+ T-cell lymphoma Inhibition of apoptosis Induction of cellular proliferation Ik-1 and MZF1 transcriptionally decrease the expression of IGF-IR in ALK+ T-cell lymphoma mRNA decay is significantly hindered in ALK+ T-cell lymphoma cells |
Effects in NPM-ALK+ T-cell lymphoma |
| IGF-IR induced phosphorylation of IRS-1 in mantle cell lymphoma IGF-IR inhibition resulted in hindrance of the PI3K/AKT and JAK/STAT pathways, and increased the expression of cleaved caspase 3 and PARP |
Inhibition of apoptosis and induction of cellular proliferation | Effects in MCL | |
| IGF-I induced PI3K/AKT and ERK pathways IGF-IR/MET receptor interaction |
The mitotic potential of HL cells is highly IGF-I dependent | Effects in HL | |
| Inhibition of IGF-IR reduces activation of PI3K/AKT and ERK pathways | HL cells underwent apoptosis upon IGF-IR inhibition and proliferation was reduced; cell growth was hindered through a G2/M-phase cell cycle arrest with complete elimination of cells in the G0/G1 phase of the cell cycle. | Effects in DLBCL | |
| GH signaling | Overexpression of endogenous GH leads to an increase in the expression of IGF-I and IGF-IR, which protects lymphoma cells from apoptosis | Effects in mouse EL4 lymphoma |