title: Control of AC133/CD133 and impact on human hematopoietic progenitor cells through nucleolin.
abstract: AC133 is a prominent surface marker of CD34+ and CD34- hematopoietic stem/progenitor cell (HSPC) subsets. AC133+ HSPCs contain high progenitor cell activity and are capable of hematopoietic reconstitution. Furthermore, AC133 is used for prospective isolation of tumor-initiating cells in several hematological malignancies. Nucleolin is a multifunctional factor of growing and cancer cells, which is aberrantly active in certain hematological neoplasms, and serves as a candidate molecular target for cancer therapy. Nucleolin is involved in gene transcription and RNA metabolism and is prevalently expressed in HSPCs, as opposed to differentiated hematopoietic tissue. The present study dissects nucleolin-mediated activation of surface AC133 and its cognate gene CD133, via specific interaction of nucleolin with the tissue-dependent CD133 promoter P1, as a mechanism that crucially contributes to AC133 expression in CD34+ HSPCs. In mobilized peripheral blood (MPB)-derived HSPCs, nucleolin elevates colony-forming unit (CFU) frequencies and enriches granulocyte-macrophage CFUs. Furthermore, nucleolin amplifies long-term culture-initiating cells and also promotes long-term, cytokine-dependent maintenance of hematopoietic progenitor cells. Active β-catenin, active Akt and Bcl-2 levels in MPB-derived HSPCs are nucleolin-dependent, and effects of nucleolin on these cells partially rely on β-catenin activity. The study provides new insights into molecular network relevant to stem/progenitor cells in normal and malignant hematopoiesis.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Reister
authors.affiliation: Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Mahotka
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: R
authors.identifier: http://orcid.org/0000-0001-5230-0628
authors.initials: R
authors.lastname: Meisel
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-6121-4737
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Grinstein
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000502:physiology*; D051176:beta Catenin / Q000032:analysis / Q000502:physiology; D000097796:Nucleolin
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D010455:Peptides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D051176:beta Catenin; D000097796:Nucleolin; C495270:CTNNB1 protein, human; C000606023:PROM1 protein, human