Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/β-Catenin Activation

The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we c...

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Published in:	Cancer research (Chicago, Ill.) Vol. 77; no. 18; pp. 4846 - 4857
Main Authors:	Bhagat, Tushar D, Chen, Si, Bartenstein, Matthias, Barlowe, A Trevor, Von Ahrens, Dagny, Choudhary, Gaurav S, Tivnan, Patrick, Amin, Elianna, Marcondes, A Mario, Sanders, Mathijs A, Hoogenboezem, Remco M, Kambhampati, Suman, Ramachandra, Nandini, Mantzaris, Iaonnis, Sukrithan, Vineeth, Laurence, Remi, Lopez, Robert, Bhagat, Prafullla, Giricz, Orsi, Sohal, Davendra, Wickrema, Amittha, Yeung, Cecilia, Gritsman, Kira, Aplan, Peter, Hochedlinger, Konrad, Yu, Yiting, Pradhan, Kith, Zhang, Jinghang, Greally, John M, Mukherjee, Siddhartha, Pellagatti, Andrea, Boultwood, Jacqueline, Will, Britta, Steidl, Ulrich, Raaijmakers, Marc H G P, Deeg, H Joachim, Kharas, Michael G, Verma, Amit
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research, Inc 15-09-2017
Subjects:	Activation Animals Apoptosis Azacytidine beta Catenin - metabolism Bone marrow Cancer CD34 antigen Cell Differentiation Cell Proliferation CpG Islands Cytosine DNA Methylation DNA methyltransferase Epigenesis, Genetic Epigenetics Erythrocytes Hematopoiesis Hematopoietic Stem Cells - metabolism Hematopoietic Stem Cells - pathology Humans Leukemogenesis Mesenchymal Stromal Cells - metabolism Mesenchymal Stromal Cells - pathology Mesenchyme Methylation Mice Mice, Transgenic Myelodysplastic syndrome Myelodysplastic Syndromes - genetics Myelodysplastic Syndromes - metabolism Myelodysplastic Syndromes - pathology Myeloid cells Oncogene Proteins, Fusion - genetics Rodents Stromal cells Tumor Cells, Cultured Wnt protein Wnt Proteins - metabolism β-Catenin
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Summary:	The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands. Stroma derived from 5-azacytidine-treated patients lacked aberrant methylation and DNMTi treatment of primary MDS stroma enhanced its ability to support erythroid differentiation. An integrative expression analysis revealed that the WNT pathway antagonist FRZB was aberrantly hypermethylated and underexpressed in MDS stroma. This result was confirmed in an independent set of sorted, primary MDS-derived mesenchymal cells. We documented a WNT/β-catenin activation signature in CD34 cells from advanced cases of MDS, where it associated with adverse prognosis. Constitutive activation of β-catenin in hematopoietic cells yielded lethal myeloid disease in a NUP98-HOXD13 mouse model of MDS, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment, which lead to β-catenin activation and disease progression of MDS. .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Equal Contribution
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-17-0282