Abstract
BackgroundInsulin like growth factor binding protein 7 (IGFBP7) is a secreted protein binding insulin like growth factor 1 (IGF-1), insulin, vascular endothelial growth factor A (VEGFA), and activin A. It antagonizes bone morphogenetic proteins and is involved in the tumour propagation of solid as well as haematological malignancies. Its role in multiple myeloma (MM) is not defined so far. We therefore aim here to investigate its prognostic and pathophysiological role in MM.MethodsThe clinical significance of IGFBP7 gene expression was investigated by gene expression profiling in two independent cohorts (n = 948) of newly-diagnosed MM patients. Methylation of the IGFBP7 promoter was analysed by pyrosequencing and treatment of MM cell lines with 5-aza-2-deoxycytidine. The impact of IGFBP7 on MM cells was studied by CCK-8 assay, BrdU assay and flow cytometry, respectively. IGFBP7 expression in bone marrow stromal cells (BMSCs) was studied by quantitative RT-PCR. For osteoblast development, immortalized and primary human BMSCs were cultured in osteogenic differentiation medium for 7–14 days in the presence of recombinant human IGFBP7 and/or activin A.ResultsMedian IGFBP7 expression is significantly lower in CD138-purified plasma cells from individuals with MGUS and MM, compared to normal bone marrow plasma cells. IGFBP7 gene expression in MM cells is regulated by methylation, shown by pyrosequencing and exposure to demethylating agents (5-aza-2-deoxycytidine). High expression of IGFBP7 in MM cells is associated with adverse survival in two independent cohorts of 247 and 701 newly-diagnosed MM patients treated with high-dose therapy and autologous stem cell transplantation. IGFBP7 is associated with prognostically adverse chromosomal aberrations (t(4;14) and gain of 1q21), MMSET expression, and higher myeloma cell proliferation. In vitro, IGFBP7 overcomes activin A induced osteoblast suppression and promotes osteogenesis. MM cells downregulate IGFBP7 in stromal cells, possibly contributing to the osteoblast suppression found in MM. Conversely, higher IGFBP7 expression is associated with a lower probability of myeloma bone disease.ConclusionsOur data indicate that IGFBP7 expression is a marker for a specific methylation pattern in myeloma, linked to translocation t(4;14) associated MMSET expression, showing clinical features of adverse prognosis with absence of myeloma bone disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0105-1) contains supplementary material, which is available to authorized users.
Highlights
Insulin like growth factor binding protein 7 (IGFBP7) is a secreted protein binding insulin like growth factor 1 (IGF-1), insulin, vascular endothelial growth factor A (VEGFA), and activin A
IGFBP7 gene expression is downregulated in myeloma cells IGFBP7 gene expression levels were significantly decreased in a series (HM group) of CD138 sorted plasma cells from monoclonal gammopathy of unknown significance (MGUS) (n = 22) and MM patient samples (n = 332) as well as in human myeloma cell lines (HMCLs) (n = 32) compared to normal plasma cells (n = 10) (P < 0.02) whereas IGFBP7 expression was absent in memory B cells (MBCs) and proliferating polyclonal plasmablastic cells (PPCs) (Figure 1A)
IGFBP7 gene expression was detectable in 100% of purified bone marrow plasma cells from healthy individuals, compared to 45.5% of samples from MGUS patients, 47.7% from MM patients, 47.1% of HMCLs and 0% of MBCs and PPCs, respectively
Summary
Insulin like growth factor binding protein 7 (IGFBP7) is a secreted protein binding insulin like growth factor 1 (IGF-1), insulin, vascular endothelial growth factor A (VEGFA), and activin A. It antagonizes bone morphogenetic proteins and is involved in the tumour propagation of solid as well as haematological malignancies. Direct interactions between myeloma cells and bone marrow stromal cells (BMSCs) or osteoclasts [3] as well as the crosstalk through various soluble factors play a major role in the pathophysiology of MM leading to clinical features such as myeloma bone disease, anaemia and immunosuppression [1]. An imbalance of the RANKL to OPG ratio promotes osteoclast activation [8] while the secretion of osteoblast inhibitory molecules such as DKK-1 and activin A impairs osteogenesis, leading to myeloma induced bone disease [9,10]
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