Abstract
Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment.
Highlights
Multiple myeloma (MM) is one of the most common hematologic malignancies and is characterized by an uncontrolled clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM)
gene expression profiling (GEP) data from five different datasets underwent our statistical analysis: (1) GSE47552(ref. 2) including GEP data from purified CD138+ cells from BM of five healthy donors, 20 monoclonal gammopathy of undetermined significance (MGUS), 33 smoldering MM (sMM) and 41 newly diagnosed MM patients; (2) GSE9782(ref. 14) including GEP data from 264 pretreated patients enrolled in phase II and III bortezomib trials; (3) GSE24080(ref. 15) including GEP data from 559 newly diagnosed MM treated with total therapy (TT) 2 or 3; (4) GSE57317(ref. 16) including GEP data from 55 pretreated patients enrolled in TT6 phase II clinical trial; and (5) GSE2658 including GEP data from 559 chemo-naive patients enrolled in TT2 and TT3 clinical trials
We investigated the role of 20 inflammation-related genes in predicting disease evolution and MM patients’ survival
Summary
Multiple myeloma (MM) is one of the most common hematologic malignancies and is characterized by an uncontrolled clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). Lacking the clinical features of symptomatic disease, both MGUS and sMM patients carry the same initial mutations and most of the chromosomal abnormalities of overt MM, suggesting that these events are necessary but not sufficient for disease progression.[3,4] The evolution from MGUS to sMM and to MM relies on further complex conditions that include genomic instability, epigenetic and microenvironmental signals.[2,4,5] The interplay between MM cells and the BM microenvironment (BMM) is currently under active investigation, and different studies have pointed out its role in both disease pathogenesis and progression.[3,6] MM cells grow and proliferate almost exclusively within the BM, where they produce an inflammatory/ immunosuppressive milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune escape.[7,8,9]
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