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Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

Justyna A. Wierzbinska, Reka Toth, Naveed Ishaque, Karsten Rippe, Jan-Philipp Mallm, Lara Klett, Daniel Mertens, Thorsten Zenz, Thomas Hielscher, Marc Seifert, Ralf Küppers, Yassen Assenov, Pavlo Lutsik, Stephan Stilgenbauer, Philipp M. Roessner, Martina Seiffert, John Byrd, Christopher C. Oakes, Christoph Plass, View ORCID ProfileDaniel B. Lipka
doi: https://doi.org/10.1101/2020.02.04.933937
Justyna A. Wierzbinska
1Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
2Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
3The German Cancer Consortium (DKTK)
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Reka Toth
1Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Naveed Ishaque
3The German Cancer Consortium (DKTK)
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Karsten Rippe
3The German Cancer Consortium (DKTK)
4Division of Chromatin Networks, DKFZ, Heidelberg, Germany
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Jan-Philipp Mallm
3The German Cancer Consortium (DKTK)
4Division of Chromatin Networks, DKFZ, Heidelberg, Germany
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Lara Klett
3The German Cancer Consortium (DKTK)
4Division of Chromatin Networks, DKFZ, Heidelberg, Germany
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Daniel Mertens
3The German Cancer Consortium (DKTK)
5Mechanisms of Leukemogenesis, DKFZ, Heidelberg, Germany
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Thorsten Zenz
6Experimental Hematology Lab, University Hospital Zurich, Switzerland
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Thomas Hielscher
7Biostatistics, DKFZ, Heidelberg, Germany
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Marc Seifert
8Group Molecular Genetics, Essen University Hospital, Essen, Germany
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Ralf Küppers
8Group Molecular Genetics, Essen University Hospital, Essen, Germany
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Yassen Assenov
1Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Pavlo Lutsik
1Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Stephan Stilgenbauer
9Department of Internal Medicine, Ulm University, Ulm, Germany
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Philipp M. Roessner
10Division of Molecular Genetics, DKFZ, Heidelberg, Germany
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Martina Seiffert
10Division of Molecular Genetics, DKFZ, Heidelberg, Germany
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John Byrd
11Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, USA
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Christopher C. Oakes
11Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, USA
12Department of Biomedical Informatics, The Ohio State University, Columbus, USA
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Christoph Plass
1Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
3The German Cancer Consortium (DKTK)
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  • For correspondence: c.plass@dkfz.de d.lipka@dkfz.de
Daniel B. Lipka
3The German Cancer Consortium (DKTK)
13Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
14National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
15Faculty of Medicine, Medical Center, Otto-von-Guericke-University, 39120 Magdeburg, Germany
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  • ORCID record for Daniel B. Lipka
  • For correspondence: c.plass@dkfz.de d.lipka@dkfz.de
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ABSTRACT

Background In cancer, normal epigenetic patterns are disturbed and contribute to gene expression changes, disease onset and progression. The cancer epigenome is composed of the epigenetic patterns present in the tumor-initiating cell at the time of transformation, and the tumor-specific epigenetic alterations that are acquired during tumor initiation and progression. The precise dissection of these two components of the tumor epigenome will facilitate a better understanding of the biological mechanisms underlying malignant transformation. Chronic lymphocytic leukemia (CLL) originates from differentiating B cells, which undergo extensive epigenetic programming. This poses the challenge to precisely determine the epigenomic ground-state of the cell-of-origin in order to identify CLL-specific epigenetic aberrations.

Methods We developed a linear regression model, methylome-based cell-of-origin modeling (Methyl-COOM), to map the cell-of-origin for individual CLL patients based on the continuum of epigenomic changes during normal B cell differentiation.

Results Methyl-COOM accurately maps the cell-of-origin of CLL and identifies CLL-specific aberrant DNA methylation events that are not confounded by physiologic epigenetic B cell programming. Furthermore, Methyl-COOM unmasks abnormal action of transcription factors, altered super-enhancer activities, and aberrant transcript expression in CLL. Among the aberrantly regulated transcripts were many genes that have previously been implicated in T cell biology. Flow cytometry analysis of these markers confirmed their aberrant expression on malignant B cells at the protein level.

Conclusions Methyl-COOM analysis of CLL identified disease-specific aberrant gene regulation. The aberrantly expressed genes identified in this study might play a role in immune-evasion in CLL and might serve as novel targets for immunotherapy approaches. In summary, we propose a novel framework for in silico modeling of reference DNA methylomes and for the identification of cancer-specific epigenetic changes, a concept that can be broadly applied to other human malignancies.

Footnotes

  • ↵# Joint senior authors

  • https://github.com/justannwska/Methyl-COOM

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL
Justyna A. Wierzbinska, Reka Toth, Naveed Ishaque, Karsten Rippe, Jan-Philipp Mallm, Lara Klett, Daniel Mertens, Thorsten Zenz, Thomas Hielscher, Marc Seifert, Ralf Küppers, Yassen Assenov, Pavlo Lutsik, Stephan Stilgenbauer, Philipp M. Roessner, Martina Seiffert, John Byrd, Christopher C. Oakes, Christoph Plass, Daniel B. Lipka
bioRxiv 2020.02.04.933937; doi: https://doi.org/10.1101/2020.02.04.933937
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Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL
Justyna A. Wierzbinska, Reka Toth, Naveed Ishaque, Karsten Rippe, Jan-Philipp Mallm, Lara Klett, Daniel Mertens, Thorsten Zenz, Thomas Hielscher, Marc Seifert, Ralf Küppers, Yassen Assenov, Pavlo Lutsik, Stephan Stilgenbauer, Philipp M. Roessner, Martina Seiffert, John Byrd, Christopher C. Oakes, Christoph Plass, Daniel B. Lipka
bioRxiv 2020.02.04.933937; doi: https://doi.org/10.1101/2020.02.04.933937

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