title: Up-regulation of ribosomal genes is associated with a poor response to azacitidine in myelodysplasia and related neoplasms.
abstract: Azacitidine (AZA) is a hypomethylating drug used to treat disorders associated with myelodysplasia and related neoplasms. Approximately 50 % of patients do not respond to AZA and have very poor outcomes. There is thus great interest in identifying predictive biomarkers for AZA responsiveness. We searched for specific genes whose expression level was associated with response status. Using microarrays, we analyzed gene expression patterns in bone marrow CD34+cells in serial samples from 32 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia with myelodysplasia-related changes before and during the AZA therapy. At baseline, a comparison of the responders and non-responders showed 52 differentially expressed genes (P < 0.01). Functional annotation of the deregulated genes revealed categories primarily related to ribosomes and pathways associated with proliferation. The expression level of RPL28 correlated with overall survival. We identified altered expression in 167 genes in responders, 26 genes in non-responders with stable disease, and 13 genes in non-responders with disease progression using paired t test of expression levels in patients before and during treatment. Our data indicate that AZA treatment failure is associated with the up-regulation of ribosomal genes/pathways that are likely related to intensive proteosynthesis in proliferative/neoplastic cells of non-responders.
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic. monika.belickova@uhkt.cz.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-9158-881X
authors.initials: M
authors.lastname: Monika Belickova
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
authors.forename: Michaela Dostalova
authors.initials: MD
authors.lastname: Merkerova
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Votavova
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Valka
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Vesela
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Pejsova
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hajkova
authors.affiliation: Department of Computer Science, Faculty of Electrical Engineering, Czech Technical University, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Klema
authors.affiliation: Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Cermak
authors.affiliation: 1st Department of Medicine, General University Hospital Prague, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Jonasova
mesh_terms: D001374:Azacitidine / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects*; D017211:Treatment Failure; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D012269:Ribosomal Proteins; D001374:Azacitidine
keywords: Azacitidine; Gene expression profiling; Myelodysplastic syndromes; Ribosomal genes