Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation

Tushar D. Bhagat, Si Chen, Matthias Bartenstein, A. Trevor Barlowe, Dagny Von Ahrens, Gaurav S. Choudhary, Patrick Tivnan, Elianna Amin, A. Mario Marcondes, Mathijs A. Sanders, Remco M. Hoogenboezem, Suman Kambhampati, Nandini Ramachandra, Ioannis Mantzaris, Vineeth Sukrithan, Remi Laurence, Robert Lopez, Prafullla Bhagat, Orsolya Giricz, Davendra SohalAmittha Wickrema, Cecilia Yeung, Kira Gritsman, Peter Aplan, Konrad Hochedlinger, Yiting Yu, Kith Pradhan, Jinghang Zhang, John M. Greally, Siddhartha Mukherjee, Andrea Pellagatti, Jacqueline Boultwood, Britta Will, Ulrich G. Steidl, Marc H.G.P. Raaijmakers, H. Joachim Deeg, Michael G. Kharas, Amit K. Verma

Research output: Contribution to journalArticle

15 Citations (Scopus)

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/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.

Original languageEnglish (US)
Pages (from-to)4846-4857
Number of pages12
JournalCancer Research
Volume77
Issue number18
DOIs
StatePublished - Sep 15 2017

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Catenins
Myelodysplastic Syndromes
Bone Marrow
Methyltransferases
Disease Progression
CpG Islands
Cytosine
DNA
Hematopoiesis
DNA Methylation
Stromal Cells
Epigenomics
Bone and Bones

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bhagat, T. D., Chen, S., Bartenstein, M., Barlowe, A. T., Von Ahrens, D., Choudhary, G. S., ... Verma, A. K. (2017). Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation. Cancer Research, 77(18), 4846-4857. https://doi.org/10.1158/0008-5472.CAN-17-0282

Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation. / 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, Ioannis; Sukrithan, Vineeth; Laurence, Remi; Lopez, Robert; Bhagat, Prafullla; Giricz, Orsolya; 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 G.; Raaijmakers, Marc H.G.P.; Deeg, H. Joachim; Kharas, Michael G.; Verma, Amit K.

In: Cancer Research, Vol. 77, No. 18, 15.09.2017, p. 4846-4857.

Research output: Contribution to journalArticle

Bhagat, TD, Chen, S, Bartenstein, M, Barlowe, AT, Von Ahrens, D, Choudhary, GS, Tivnan, P, Amin, E, Marcondes, AM, Sanders, MA, Hoogenboezem, RM, Kambhampati, S, Ramachandra, N, Mantzaris, I, Sukrithan, V, Laurence, R, Lopez, R, Bhagat, P, Giricz, O, Sohal, D, Wickrema, A, Yeung, C, Gritsman, K, Aplan, P, Hochedlinger, K, Yu, Y, Pradhan, K, Zhang, J, Greally, JM, Mukherjee, S, Pellagatti, A, Boultwood, J, Will, B, Steidl, UG, Raaijmakers, MHGP, Deeg, HJ, Kharas, MG & Verma, AK 2017, 'Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation', Cancer Research, vol. 77, no. 18, pp. 4846-4857. https://doi.org/10.1158/0008-5472.CAN-17-0282
Bhagat TD, Chen S, Bartenstein M, Barlowe AT, Von Ahrens D, Choudhary GS et al. Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation. Cancer Research. 2017 Sep 15;77(18):4846-4857. https://doi.org/10.1158/0008-5472.CAN-17-0282
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, Ioannis ; Sukrithan, Vineeth ; Laurence, Remi ; Lopez, Robert ; Bhagat, Prafullla ; Giricz, Orsolya ; 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 G. ; Raaijmakers, Marc H.G.P. ; Deeg, H. Joachim ; Kharas, Michael G. ; Verma, Amit K. / Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation. In: Cancer Research. 2017 ; Vol. 77, No. 18. pp. 4846-4857.
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title = "Epigenetically aberrant stroma in MDS propagates disease via Wnt/β-catenin activation",
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/b-catenin activation signature in CD34{\th} 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.",
author = "Bhagat, {Tushar D.} and Si Chen and Matthias Bartenstein and Barlowe, {A. Trevor} and {Von Ahrens}, Dagny and Choudhary, {Gaurav S.} and Patrick Tivnan and Elianna Amin and Marcondes, {A. Mario} and Sanders, {Mathijs A.} and Hoogenboezem, {Remco M.} and Suman Kambhampati and Nandini Ramachandra and Ioannis Mantzaris and Vineeth Sukrithan and Remi Laurence and Robert Lopez and Prafullla Bhagat and Orsolya Giricz and Davendra Sohal and Amittha Wickrema and Cecilia Yeung and Kira Gritsman and Peter Aplan and Konrad Hochedlinger and Yiting Yu and Kith Pradhan and Jinghang Zhang and Greally, {John M.} and Siddhartha Mukherjee and Andrea Pellagatti and Jacqueline Boultwood and Britta Will and Steidl, {Ulrich G.} and Raaijmakers, {Marc H.G.P.} and Deeg, {H. Joachim} and Kharas, {Michael G.} and Verma, {Amit K.}",
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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, Ioannis

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 G.

AU - Raaijmakers, Marc H.G.P.

AU - Deeg, H. Joachim

AU - Kharas, Michael G.

AU - Verma, Amit K.

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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