title: Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine.
abstract: Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammation-related changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosisin vitro. To provide insights intoin vivoeffects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement within vitroexperiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC.
authors.affiliation: Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic , Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Moudra
authors.affiliation: Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic; Laboratory of Molecular Therapy, Institute of Biotechnology, v.v.i., Academy of Sciences of the Czech Republic, BIOCEV, Vestec, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Hubackova
authors.affiliation: Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic , Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Machalova
authors.affiliation: Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic , Prague, Czech Republic.
authors.forename: Marketa
authors.initials: M
authors.lastname: Vancurova
authors.affiliation: Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic; Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Medical Biochemistry and Biophysics, Science For Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute, Solna, Sweden.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Department of Transgenic Models of Diseases, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic; Immunology Unit, Czech Center for Phenogenomics, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Reinis
authors.affiliation: Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic , Prague, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Hodny
authors.affiliation: 1st Department of Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital , Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Jonasova
keywords: 5-azacytidine; DNA damage; bone marrow plasma; cytokines; inflammation; myelodysplastic syndromes