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Significant up-regulation of CXCR4 in CD34+ mesenchymal stromal cells in patients with primary myelofibrosis

Primary myelofibrosis (PMF) is the rarest and the most severe stem cell derived Philadelphia chromosome-negative chronic myeloproliferative neoplasia (MPN). PMF is characterized by marrow fibrosis, leukoerythroblastosis, teardrop poikilocytosis, extramedullary hematopoesis, splenomegaly and elevated number of CD34+ cells in peripheral blood (PB). Discovery of single point mutation in the tyrosine kinase JAK2 (JAK2 V617F) has explained etiology of PV but not development of PMF or ET. Etiology of PMF is still unknown. Mobilization of hematopoietic progenitors from bone marrow (BM) to spleen and liver suggests that alternations in the cross talk between hematopoietic and stromal cells are responsible for this disease. In BM stromal, osteoclasts and endothelial cells compose a niche that controls hematopoietic homeostasis. We examined changes in expression of these 6 genes in stromal cells of patients with PMF and healthy individuals to get closer to an explanation for development of this disease, to see if bone marrow niches are altered in specific way and why is stem cell homing changed.   Secreted protein and rich in cystein, SPARC (osteonectin, BM-40) is a member of a family of matricellular protein, whose function is to modulate cell-matrix interactions and cell function without participating in the structural scaffold of the extracellular matrix. In cancer, there is no unifying model which explains all facets of its function and contribution to development and progression of cancer. Some studies have suggested that changes in methylation status of the SPARC promoter may be a mechanism that contributes to its repressed expression, leading to malignancy. Cyclooxygenase-2 gene (COX- 2) is dramatically expressed in response to exposure to inflammatory stimuli. CXCR4 gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. The transcription factor Pax-5 occupies a central role in B cell differentiation and has been implicated in the development of B cell lymphoma. The transcriptional activation function of Pax-5 requires an intact N-terminal DNA-binding domain and is strongly influenced by the C-terminal transactivation domain. HIF1-α is an important mediator of the hypoxic response of tumor cells and controls the up- regulation of a number of factors important for solid tumor expansion including the angiogenic factor VEGF. FOS encodes leucine zipper proteins wich help to form transcription factor complex AP-1 and therby regulate cell proliferation, differentiation and transformation.

stromal cells; SPARC; CXCR4; primary myelofibrosis; microenviroment

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