Abstract
Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, but the underlying molecular mechanisms remain incompletely understood. Here, we investigated the role of lysyl oxidase-like 2 (LOXL2), an enzyme involved in extracellular matrix remodeling, in PMF pathogenesis. Analysis of bone marrow cells from PMF patients revealed significantly elevated LOXL2 mRNA expression compared to healthy controls, which was further validated using 2 independent Gene Expression Omnibus datasets (GSE26049 and GSE12234). Serum LOXL2 protein levels were markedly increased in PMF patients (n = 38) compared to controls (n = 15) (P < .01), accompanied by significantly enhanced enzymatic activity (P < .05). Clinical analysis demonstrated that high LOXL2 enzyme activity correlated with adverse clinical features, including higher risk scores in both International Prognostic Scoring System (P = .029) and Dynamic International Prognostic Scoring System (P = .012) systems, and increased peripheral blood blast percentages (≥1%, P = .019). Notably, elevated LOXL2 enzyme activity emerged as an independent adverse prognostic factor in multivariate analysis. Gene set enrichment analysis revealed LOXL2's association with multiple biological processes, including extracellular matrix remodeling, inflammatory responses, and JAK-STAT signaling pathways. Using CellMiner drug prediction analysis, we identified several FDA-approved drugs, particularly kinase inhibitors, as potential LOXL2-targeting therapeutics. Our findings demonstrate LOXL2's critical role in PMF pathogenesis and suggest its potential as both a prognostic marker and therapeutic target in PMF treatment.