Whole-blood transcriptional profiling of interferon-inducible genes identifies highly upregulated IFI27 in primary myelofibrosis

Abstract

Gene expression profiling studies have unraveled deregulation of several genes that might be of pathogenetic importance for the development and phenotype of the Philadelphia-negative chronic myeloproliferative neoplasms. In the context of interferon-alpha2 as a promising therapeutic agent, we focused upon the transcriptional profiling of interferon-associated genes in patients with essential thrombocythemia (ET) (n = 19), polycythemia vera (PV) (n = 41), and primary myelofibrosis (PMF) (n = 9). Using whole-blood transcriptional profiling and accordingly obtaining an integrated signature of genes expressed in several immune cells (granulocytes, monocytes, B cells, T cells, platelets), we have identified a number of interferon-associated genes to be significantly deregulated but with a highly significant deregulation of interferon-inducible gene 27 (IFI27) (ET, PV, and PMF, fold change 8, 16, and 30, respectively). The striking deregulation of IFI genes may reflect a hyperstimulated but insufficient immune system being most enhanced in patients with advanced myelofibrosis, in whom the IFI27 gene displayed an exceedingly high expression. The interferon signature may reflect primary myelofibrosis as the burn-out phase of chronic inflammation which ultimately elicits clonal evolution and expansion owing to an exaggerated but incompetent antitumor immune response. Finally, IFI27 may be a novel biomarker of disease activity and tumor burden in patients with CMPNs.

Aberrant DNA methylation profile of chronic and transformed classic Philadelphia-negative myeloproliferative neoplasms

“…Despite the limited number of DMR found in MPN, our results suggest that aberrantly methylated genes in MPNs are involved in important signal transduction pathways such as NF-κB associated networks (Online Supplementary Figure S5). This was not only indicated by the ingenuity pathway analysis of our samples but was also supported when we applied the same analysis to publicly available expression data 39 (P=3.02E-02). Deregulation of NF-κB signaling cascade has been described in myeloid and lymphoid neoplasias, correlating its degree of activation with the risk of progression from MDS to AML.…”

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

“…Intriguingly, GATA1 mRNA expression in megakaryocytes [28], blood CD341 progenitors [29], and mononuclear BM cells [30] were found to be similar in PMF compared with control subjects. Novel information from the NCBI/GEO database has even shown higher GATA1 mRNA expression in whole blood and granulocytes from PMF patients compared with controls (GEO Accession: GSE26049 and GSE54646, unpublished results) [31,32]. GATA1 may also be present in endothelial cells [14], but we could not verify expression in our BM biopsy vessels.…”

Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?

“…[6][7][8][9][10][11][12][13][16][17][18] Because biomarkers of chronic inflammation are elevated in MPN patients, 3 chronic inflammation may not only have an impact on the risk of thrombosis but also facilitating clonal expansion mediated via high levels of TNF-␣ in the bone marrow. 64 Most recently, gene expression profiling studies have unraveled massive deregulation of a number of genes involved in immune regulation and inflammation, 50,51 adding to the concept that chronic inflammation and immune deregulation may be important in the pathogenesis and progression of these neoplasms. 50,51 Irrespective of the underlying mechanisms for aberrant inflammatory and immune function, deregulation of inflammation and immune genes may drive clonal myeloproliferation and evolution toward the myelofibrotic burnt-out phase of the disease.…”

“…64 Most recently, gene expression profiling studies have unraveled massive deregulation of a number of genes involved in immune regulation and inflammation, 50,51 adding to the concept that chronic inflammation and immune deregulation may be important in the pathogenesis and progression of these neoplasms. 50,51 Irrespective of the underlying mechanisms for aberrant inflammatory and immune function, deregulation of inflammation and immune genes may drive clonal myeloproliferation and evolution toward the myelofibrotic burnt-out phase of the disease. Ultimately, the abnormal immune homeostasis may imply a defective tumor immune surveillance, which may contribute to the increased frequency of second cancer as well.…”