Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Genome medicine - 12(2020), 1 vom: 18. März, Seite 29 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wierzbinska, Justyna A [VerfasserIn] |
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| Links: |
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| Themen: |
Cell-of-origin |
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| Anmerkungen: |
Date Completed 04.01.2021 Date Revised 04.01.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s13073-020-00724-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM307749746 |
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| 100 | 1 | |a Wierzbinska, Justyna A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL |
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| 500 | |a Date Revised 04.01.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cell-of-origin | |
| 650 | 4 | |a Chronic lymphocytic leukemia | |
| 650 | 4 | |a DNA methylation | |
| 650 | 4 | |a T cell antigens | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 700 | 1 | |a Toth, Reka |e verfasserin |4 aut | |
| 700 | 1 | |a Ishaque, Naveed |e verfasserin |4 aut | |
| 700 | 1 | |a Rippe, Karsten |e verfasserin |4 aut | |
| 700 | 1 | |a Mallm, Jan-Philipp |e verfasserin |4 aut | |
| 700 | 1 | |a Klett, Lara C |e verfasserin |4 aut | |
| 700 | 1 | |a Mertens, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Zenz, Thorsten |e verfasserin |4 aut | |
| 700 | 1 | |a Hielscher, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Seifert, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Küppers, Ralf |e verfasserin |4 aut | |
| 700 | 1 | |a Assenov, Yassen |e verfasserin |4 aut | |
| 700 | 1 | |a Lutsik, Pavlo |e verfasserin |4 aut | |
| 700 | 1 | |a Stilgenbauer, Stephan |e verfasserin |4 aut | |
| 700 | 1 | |a Roessner, Philipp M |e verfasserin |4 aut | |
| 700 | 1 | |a Seiffert, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Byrd, John |e verfasserin |4 aut | |
| 700 | 1 | |a Oakes, Christopher C |e verfasserin |4 aut | |
| 700 | 1 | |a Plass, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Lipka, Daniel B |e verfasserin |4 aut | |
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