engleski

Expression of a set of cell-stroma interacting genes in patients with primary myelofibrosis

Background: Primary myelofibrosis (PMF) is stem cell derived Philadelphia chromosome-negative chronic myeloproliferative neoplasia characterized by marrow fibrosis, leukoerythroblastosis, extramedullary hematopoiesis and splenomegaly. Etiology is still unknown, but mutations in several genes are found at increased frequency (e.g. JAK2, MPL, TET2, IKAROS) in this disease. The therapy for PMF is unsatisfactory and median survival is poor. Different medications have, therefore, been evaluated in clinical trials, including novel JAK2 inhibitors, and immunomodulatory inhibitory drugs (IMiDs) like thalidomide and lenalidomide. Aim: To assess genes that impact PMF, we analyzed expression of genes that are involved in cell-stroma adhesion (SPARC, CXCR4), metabolism (COX-2, HIF1), differentiation and signaling (Pax5 and Socs3) in mononuclear cells (MNC) from bone marrow (BM) or peripheral blood (PB) of 32 PMF patients before and after treatment with the combination of lenalidomide and prednisone. Methods: PB and BM aspirate samples from healthy individuals and PMF patients were ficolled and RNA was isolated from MNCs with Trizol reagent.Q-RT-PCR was performed to measure the expression levels of SPARC, COX-2, CXCR4, Pax5, Socs3 and HIF1 transcripts with β -actin as internal control. Results: Pre-therapy, SPARC and COX-2 expression were decreased in BM MNC, while CXCR4, Pax5 and HIF1 were increased, compared to controls. At the same time, COX-2, CXCR4 and HIF1 expression were decreased in PB MNC. No correlations between gene expression and JAK2 mutational status or cytogenetic abnormalities were found. Six months after treatment with lenalidomide/prednisone further decrease in SPARC, Socs3 and HIF1 in BM MNC was recorded, and COX-2 and CXCR4 further decreased in PB MNC. No correlation with response was found. Summary/ conclusion: Pre-therapy down regulation of SPARC may indicate its defect in tumor suppressing activity in PMF. Interestingly, lenalidomide treatment known for the dramatic up-regulation of SPARC expression in patients with 5q- myelodysplastic syndrome, did not show the same pattern in PMF. Further investigation of the SPARC regulation in stromal and other elements of hematopoietic niche of PMF is underway.

expression; cell-stroma genes; primary myelofibrosis

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