Proteolytic Matrix Metallopeptidases and Inhibitors in BCR-ABL1-Negative Myeloproliferative Neoplasms: Correlation with JAK2^V617F Mutation Status

Abstract

Background/Aims: Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) share the same acquired lesion JAK2^V617F and may exhibit substantial overlap. Variability in JAK activation and allele burden, complemented by host, genetic and non-genetic modifiers, determine the phenotype. The aim of this study was to investigate the presence of the JAK2 mutation in association with the ratio of metallopeptidases inhibitors (TIMPs) to tissue metallopeptidases (MMPs) in MPNs, where inhibitory rather than proteolytic activity in marrow microenvironment appears to predominate. Methods: 94 patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis, and 102 healthy individuals were evaluated. Allele-specific PCR and RFLP were used to detect JAK2 and genomic status. Serum concentrations of MMP and TIMP were measured by ELISA. The parameters were assessed with covariance analysis, and adjusted for gender, age and co-morbidity. Results: Mutation frequency was 81.91%. Abnormal TIMP/MMP ratios were identified in all three diseases. JAK2 mutation was correlated with significant changes in TIMP concentrations. Conclusions: Identification of an abnormal TIMP/MMP ratio in all three diseases, regardless of the JAK2 status, indicates invariable marrow remodeling. In this particular group of patients, presence of a JAK2^V617F mutation, being associated with even higher ratios, appears to be a concurring participant in bone marrow-reforming processes. Additional research may delineate correlates with the JAK2 allelic burden.

The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression

“…Furthermore, these chimeras were able to suppress TNF-α and HB-EGF shedding in cell-based assays and had no growth-promoting activity in vitro. Instead, these chimeras inhibited cell migration and motility in several cancer cell lines [ 242 ]. Overall these findings suggest that engineering selective TIMPs with refined specificity against specific metzincin members may form the basis for developing novel therapeutics against cancer.…”

“…Maintaining MMP:TIMP balance is crucial for the maintenance of tissue homeostasis [ 165 ]. MMP:TIMP balance has been shown to contribute to tumor progression [ 242 ]. Recently, an unbalanced expression of MMP:TIMP axis genes in tumors were correlated with aberrant epigenotype in various gene promoters [ 243 ].…”

Expressão gênica de metaloproteinases e de seus reguladores em neoplasias mieloproliferativas: associação com biomarcadores de angiogênese e <i>status</i> mutacional

“…(allele burden) nesses pacientes (Vadikolia et al, 2011). Nosso estudo mostrou que as altas concentrações de proteínas encontradas nos pacientes JAK2 V617F positivos não foram associadas à carga alélica desta mutação.…”