دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL
المؤلفون: Justyna A. Wierzbinska, Reka Toth, Naveed Ishaque, Karsten Rippe, Jan-Philipp Mallm, Lara C. 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
المصدر: Genome Medicine, Vol 12, Iss 1, Pp 1-19 (2020)
بيانات النشر: BMC, 2020.
سنة النشر: 2020
المجموعة: LCC:Medicine
LCC:Genetics
مصطلحات موضوعية: DNA methylation, Cell-of-origin, Chronic lymphocytic leukemia, T cell antigens, Medicine, Genetics, QH426-470
الوصف: 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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1756-994X
Relation: http://link.springer.com/article/10.1186/s13073-020-00724-7; https://doaj.org/toc/1756-994X
DOI: 10.1186/s13073-020-00724-7
URL الوصول: https://doaj.org/article/07bff21ec86d48ca9abc2144570ae521
رقم الأكسشن: edsdoj.07bff21ec86d48ca9abc2144570ae521
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:1756994X
DOI:10.1186/s13073-020-00724-7