Single-Gene Analysis Deciphers Protein Role in Regulation of ECM Genes in MPNs

The protein human interferon (IFN) alpha-2 influences the regulation of several extracellular matrix (ECM) genes involved in tissue remodeling and repair after tissue injury in polycythemia vera (PV) and other related neoplasms, according to a presentation at the 14th International Congress on Myeloproliferative Neoplasms.

The study, led by Vibe Skov, PhD, of the Department of Hematology at Zealand University Hospital in Roskilde, Denmark, investigated the gene signatures of patients with PV, essential thrombocythemia (ET), and other chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs).

The investigators also provided evidence that previously reported abnormal ECM-metabolism in MPNs is accompanied by altered gene signatures in peripheral blood cells and that these gene signatures are significantly influenced by treatment with IFN.

The development of fibrosis and angiogenesis in several cancers is known to be tightly associated with chronic inflammation and ECM remodeling, which is what led the investigators to suspect that IFN impacts deregulated ECM genes in MPNs. The objective of the study was to provide a comprehensive gene signature of ECM-related proteins in MPNs and the impact of IFN on deregulated ECM genes, with particular focus on genes associated with the regulation of major stromal proteins and matrix metalloproteinases.

The study included eight patients with ET, 21 patients with PV, and four patients with primary myelofibrosis (PMF). Hydroxyurea (n=18) or anagrelide (n=6) were discontinued one week prior to enrollment. Global gene expression microarray analysis of whole blood was performed before and after three months of treatment.

Single gene analysis was performed on the Qiagen Human Extracellular matrix and adhesion molecules (ECM) 116 gene panel including all remaining collagen genes. In response to treatment with IFN, four genes were upregulated in ET, including MMP8, SELL, TIMP1, and TIMP2, and six genes were downregulated, including CD44, COL4A3BP, HAS1, SGCE, SPP1, and THBS1. In PV, five genes were upregulated, including COL8A2, CTNNA1, CTNND1, ITGA4, and SELL, and seven genes were downregulated, including CD44, COL10A1, COL4A3BP, LAMA2, MMP1, PECAM1, and THBS3. In PMF, MMP10, PECAM1, SPP1, and THBS1 were downregulated, and no genes were upregulated (P<.05 for all).

“Further studies are needed to determine whether these transcriptional changes align with concurrent changes in ECM protein metabolism as assessed in the bone marrow microenvironment and in the systemic circulation,” the investigators wrote.

Reference

Skov V, Thomassen M, Kjær L, et al. Transcriptional profiling of extracellular matrix-related genes in peripheral blood from patients with polycythemia vera and related neoplasms. Impact of interferon-alpha2. Abstract #106. Presented at the 14th International Congress on Myeloproliferative Neoplasms. October 27-28, 2022.