PF661 MOLECULAR PROFILING REVEALS HIGHLY DEREGULATED INSULIN GROWTH FACTOR BINDING PROTEINS IN PATIENTS WITH MYELOFIBROSIS AND RELATED NEOPLASMS

Abstract

Background:The Insulin Growth Factor (IGF) system has been extensively studied in polycythemia vera (PV) showing erythroid progenitors to be hypersensitive to IGF1, levels of the IGF1‐binding protein – IGFBP‐1 to be fourfold increased but normal levels of IGF1 and IGFBP3. Furthermore, the stimulatory effect of IGFBP1 on erythroid progenitors in vitro provided a connection to overproduction of red blood cells in PV through IGF1. Most lately, increased IGF‐1R expression of mononuclear cells was found in patients with Philadelphia‐negative myeloproliferative neoplasms (MPN). In addition, the JAK2V617F mutation has been shown to result in IGF1 hypersensitivity in Ba/F3 cells providing a molecular basis for significance of IGF1 signaling in MPNs.Dysregulation of the IGF system is important in cancer development. We herein for the first time demonstrate several genes of IGF system to be markedly deregulated in MPNsAims:To study whole blood gene expression profiling in patients with MPNs.Methods:Gene expression microarrays were applied to whole blood from control subjects (n = 21) and patients with ET (n = 19), PV (n = 41), and PMF (n = 9). Affymetrix HG‐U133 2.0 Plus microarrays were used to generate gene expression profiles of 54.675 probe sets (38.500 genes). Total RNA was purified from whole‐blood, amplified to biotin‐labeled aRNA and hybridized to microarray chips. The statistical software R was applied to perform initial data processing and statistical analysis of microarray data.Results:20,439, 25,307, and 17,417 probe sets were significantly differentially expressed between control subjects and patients with ET, PV and PMF, respectively (FDR<0.05). Several of the insulin‐like growth factor (IGF) and insulin‐like growth factor binding protein (IGFBP) genes were significantly deregulated (Table 1). IGF1, IGF2, IGFALS, IGFBP2, and IGF2BP1 were significantly upregulated in all three disease entities of which IGFBP2 was progressively and significantly upregulated from ET over PV to PMF (FDR<0.05).Summary/Conclusion:In the present study we found several IGF‐related genes to be significantly deregulated in MPNs. Of note, IGF‐1 was significantly upregulated in all three subgroups of patients (ET, PV and PMF) and IGFBP1 was significantly downregulated in ET and PV patients. These observations are not in line with previous findings of normal IGF‐1 and highly elevated IGFBP1 levels in patients with PV. IGF‐1 has been shown to stimulate cell growth and up‐and down‐regulate the expression of anti‐ and pro‐apoptotic molecules, respectively, thereby protecting cancer cells from apoptosis. Enhanced IGF‐I gene expression might contribute to the chronic inflammatory state in MPN through enhancement of IL‐6 activity. It is intriguing to consider if IGF‐1 might also promote angiogenesis in MPN by stimulating VEGF secretion by e.g. megakaryocytes and monocytes similar to stimulation of VEGF‐secretion by e.g. myeloma cells. In conclusion, we have shown a number of genes in the IGF‐1 system to be deregulated in MPN, which altogether might contribute in driving clonal myeloproliferation, decreased apoptosis, bone marrow angiogenesis, immune evasion and inflammation as well. Future studies on the interplay between the transcriptome, IGF‐related proteins and IGF‐R expression levels might deliver new insight into the role of IGF‐system in the pathogenesis of MPNs and ultimately give the impetus to studies on the efficacy of inhibitors of IGF1 or IGF1R, which prohibit development of MPN‐phenotype in JAK2V617F mice.image