%0 Journal Article
%A Wierzbinska, Justyna Anna
%A Toth, Reka
%A Ishaque, Naveed
%A Rippe, Karsten
%A Mallm, Jan-Philipp
%A Klett, Lara C
%A Mertens, Daniel
%A Zenz, Thorsten
%A Hielscher, Thomas
%A Seifert, Marc
%A Küppers, Ralf
%A Assenov, Yassen
%A Lutsik, Pavlo
%A Stilgenbauer, Stephan
%A Roessner, Philipp M
%A Seiffert, Martina
%A Byrd, John
%A Oakes, Christopher C
%A Plass, Christoph
%A Lipka, Daniel
%T Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL.
%J Genome medicine
%V 12
%N 1
%@ 1756-994X
%C London
%I BioMed Central
%M DKFZ-2020-00629
%P 29
%D 2020
%Z Modyfied by adding this comment for testin purposes#EA:B340#LA:B340#
%X 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.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.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.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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:32188505
%R 10.1186/s13073-020-00724-7
%U https://inrepo02.dkfz.de/record/154170