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Ferrata Storti Foundation
Myelodysplastic Syndromes
Transforming growth factor β1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia
Haematologica 2018 Volume 103(9):1462-1471
1Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty; 2Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg and 3Department of Orthopedic Surgery, University of Duesseldorf, Medical Faculty, Germany
Stefanie Geyh,1* Manuel Rodríguez-Paredes,1,2* Paul Jäger,1 Annemarie Koch,1 Felix Bormann,2 Julian Gutekunst,2 Christoph Zilkens,3 Ulrich Germing,1 Guido Kobbe,1 Frank Lyko,2 Rainer Haas1 and Thomas Schroeder1
*SG and MR-P contributed equally to this work.
ABSTRACT
Mesenchymal stromal cells are involved in the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia, but the underlying mechanisms are incompletely understood. To further characterize the pathological phenotype we performed RNA sequencing of mesenchymal stromal cells from patients with myelodys- plastic syndromes and acute myeloid leukemia and found a specific molecular signature of genes commonly deregulated in these disorders. Pathway analysis showed a strong enrichment of genes related to osteo- genesis, senescence, inflammation and inhibitory cytokines, thereby reflecting the structural and functional deficits of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia on a molecular level. Further analysis identified transforming growth factor β1 as the most probable extrinsic trigger factor for this altered gene expres- sion. Following exposure to transforming growth factor β1, healthy mes- enchymal stromal cells developed functional deficits and adopted a phe- notype reminiscent of that observed in patient-derived stromal cells. These suppressive effects of transforming growth factor β1 on stromal cell functionality were abrogated by SD-208, an established inhibitor of transforming growth factor β receptor signaling. Blockade of transform- ing growth factor β signaling by SD-208 also restored the osteogenic dif- ferentiation capacity of patient-derived stromal cells, thus confirming the role of transforming growth factor β1 in the bone marrow microenviron- ment of patients with myelodysplastic syndromes and acute myeloid leukemia. Our findings establish transforming growth factor β1 as a rele- vant trigger causing functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia and identify SD-208 as a candidate to revert these effects.
Introduction
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are blood stem cell disorders that are characterized by hematopoietic insufficiency causing relevant morbidity and mortality. For a long time both entities have been considered to be hematopoietic-cell autonomous diseases originating from the accumulation of genetic and epigenetic alterations within the hematopoietic stem and progenitor cell (HSPC) population.1,2 Recently, it has become apparent that these myeloid disorders do not exclusively arise from HSPC but also involve the
Correspondence:
thomas.schroeder@med.uni-duesseldorf.de
Received: December 19, 2017. Accepted: May 14, 2018. Pre-published: May 17, 2018.
doi:10.3324/haematol.2017.186734
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/9/1462
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