Abstract
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. Cancer Res; 77(18); 4846-57. ©2017 AACR.
Highlights
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of acquired clonal bone marrow disorders characterized by varying degrees of cytopenias, morphologic and functional abnormalities of hematopoietic cells, and the risk of transformation into acute myeloid leukemia (AML; ref. 1)
Unsupervised clustering based on cytosine methylation profiles demonstrated that untreated myelodysplastic syndrome (MDS) stromal cells were epigenetically distinct from healthy controls (Fig. 1A), whereas MDS stromal cells from 5-Aza–treated patients clustered closer to healthy controls
We show that marrow stroma in patients with MDS is aberrantly hypermethylated and that these marks are abrogated in stroma derived from 5-Aza–treated patients
Summary
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of acquired clonal bone marrow disorders characterized by varying degrees of cytopenias, morphologic and functional abnormalities of hematopoietic cells, and the risk of transformation into acute myeloid leukemia (AML; ref. 1). Myelodysplastic syndromes (MDS) comprise a heterogeneous group of acquired clonal bone marrow disorders characterized by varying degrees of cytopenias, morphologic and functional abnormalities of hematopoietic cells, and the risk of transformation into acute myeloid leukemia Studies have traditionally focused on hematopoietic cells in an effort to understand hematologic disease development with the goal of pursuing therapeutic solutions. The hematopoietic cells in MDS have been shown to contain numerous genetic and epigenetic aberrations [2] and these studies have helped elucidate the pathobiology of MDS. There is growing evidence that microenvironmental defects contribute to ineffective hematopoiesis and, progression of the disease [3, 4]. The bone marrow microenvironment consists of a mixture of different cell types—mostly represented by stromal or. Bartenstein, and A.T. Barlowe contributed to this article
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