TY - JOUR
T1 - Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation
AU - Bhagat, Tushar D.
AU - Chen, Si
AU - Bartenstein, Matthias
AU - Barlowe, A. Trevor
AU - Von Ahrens, Dagny
AU - Choudhary, Gaurav S.
AU - Tivnan, Patrick
AU - Amin, Elianna
AU - Marcondes, A. Mario
AU - Sanders, Mathijs A.
AU - Hoogenboezem, Remco M.
AU - Kambhampati, Suman
AU - Ramachandra, Nandini
AU - Mantzaris, Iaonnis
AU - Sukrithan, Vineeth
AU - Laurence, Remi
AU - Lopez, Robert
AU - Bhagat, Prafullla
AU - Giricz, Orsolya
AU - Sohal, Davendra
AU - Wickrema, Amittha
AU - Yeung, Cecilia
AU - Gritsman, Kira
AU - Aplan, Peter
AU - Hochedlinger, Konrad
AU - Yu, Yiting
AU - Pradhan, Kith
AU - Zhang, Jinghang
AU - Greally, John M.
AU - Mukherjee, Siddhartha
AU - Pellagatti, Andrea
AU - Boultwood, Jacqueline
AU - Will, Britta
AU - Steidl, Ulrich
AU - Raaijmakers, Marc H.G.P.
AU - Deeg, H. Joachim
AU - Kharas, Michael G.
AU - Verma, Amit
N1 - Funding Information:
This work was supported by the NIH (R01s HL116336, DK103961), Leukemia and Lymphoma Society and Department of Defense (to A. Verma). M.G. Kharas was supported by the U.S. NIH National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award and NIDDKNIH R01-DK101989-01A1, Louis V Gerstner Young Investigator Award, and the American Society of Hematology Junior Scholar Award, Kimmel Scholar Award, and V-Scholar Award. M.H.G.P. Raaijmakers was supported by grants from the Dutch Cancer Society (KWF Kankerbes-trijding; EMCR 2010-4733), the Netherlands Organization of Scientific Research (NWO90700422), and the Netherlands Genomics Initiative (40-41009-98-11062). A. Pellagatti and J. Boultwood were supported by Bloodwise UK. T.D. Bhagat was supported by a fellowship grant from NYSTEM.
Publisher Copyright:
©2017 AACR.
PY - 2017/9/15
Y1 - 2017/9/15
N2 - 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/b-catenin activation signature in CD34þ cells from advanced cases of MDS, where it associated with adverse prognosis. Constitutive activation of b-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 b-catenin activation and disease progression of MDS.
AB - 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/b-catenin activation signature in CD34þ cells from advanced cases of MDS, where it associated with adverse prognosis. Constitutive activation of b-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 b-catenin activation and disease progression of MDS.
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U2 - 10.1158/0008-5472.CAN-17-0282
DO - 10.1158/0008-5472.CAN-17-0282
M3 - Article
C2 - 28684528
AN - SCOPUS:85031430256
SN - 0008-5472
VL - 77
SP - 4846
EP - 4857
JO - Cancer research
JF - Cancer research
IS - 18
ER -
