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

• 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0282

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.
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