title: Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia.
abstract: Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.|University Tumor Center Duesseldorf, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Geyh
authors.affiliation: University Tumor Center Duesseldorf, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.|Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rodríguez-Paredes
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Jäger
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Khandanpour
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: R-P
authors.initials: RP
authors.lastname: Cadeddu
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Gutekunst
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.|Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: C M
authors.initials: CM
authors.lastname: Wilk
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Fenk
authors.affiliation: Department of Orthopedic Surgery, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Zilkens
authors.affiliation: Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hermsen
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Germing
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Kobbe
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Lyko
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Haas
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schroeder
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D002135:Calcium-Binding Proteins; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D019089:Stem Cell Factor; D015675:Osteocalcin