TY  - JOUR
AU  - Wierzbinska, Justyna Anna
AU  - Toth, Reka
AU  - Ishaque, Naveed
AU  - Rippe, Karsten
AU  - Mallm, Jan-Philipp
AU  - Klett, Lara C
AU  - Mertens, Daniel
AU  - Zenz, Thorsten
AU  - Hielscher, Thomas
AU  - Seifert, Marc
AU  - Küppers, Ralf
AU  - Assenov, Yassen
AU  - Lutsik, Pavlo
AU  - Stilgenbauer, Stephan
AU  - Roessner, Philipp M
AU  - Seiffert, Martina
AU  - Byrd, John
AU  - Oakes, Christopher C
AU  - Plass, Christoph
AU  - Lipka, Daniel
TI  - Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL.
JO  - Genome medicine
VL  - 12
IS  - 1
SN  - 1756-994X
CY  - London
PB  - BioMed Central
M1  - DKFZ-2020-00629
SP  - 29
PY  - 2020
N1  - Modyfied by adding this comment for testin purposes#EA:B340#LA:B340#
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32188505
DO  - DOI:10.1186/s13073-020-00724-7
UR  - https://inrepo02.dkfz.de/record/154170
ER  -