Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2015-11-25

AUTHORS

S Geyh, M Rodríguez-Paredes, P Jäger, C Khandanpour, R-P Cadeddu, J Gutekunst, C M Wilk, R Fenk, C Zilkens, D Hermsen, U Germing, G Kobbe, F Lyko, R Haas, T Schroeder

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. More... »

PAGES

683-691

Journal

TITLE

Leukemia

ISSUE

3

VOLUME

30

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2015.325

DOI

http://dx.doi.org/10.1038/leu.2015.325

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1050370922

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26601782


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395 Department of Orthopedic Surgery, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany
396 University Tumor Center Duesseldorf, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany
397 rdf:type schema:Organization
398 grid-institutes:grid.509524.f schema:alternateName Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
399 schema:name Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
400 University Tumor Center Duesseldorf, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany
401 rdf:type schema:Organization
402 grid-institutes:grid.5718.b schema:alternateName Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
403 schema:name Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
404 rdf:type schema:Organization
405 grid-institutes:grid.7400.3 schema:alternateName Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
406 schema:name Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany
407 Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
408 rdf:type schema:Organization
 




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