TY - JOUR
T1 - Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL
AU - Wierzbinska, Justyna A.
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 B.
N1 - Funding Information:
This work was supported in part by the PRECISE consortium with funds from the German Federal Ministry of Education and Research (031L0076A), and the Helmholtz Foundation (CP, KR, DM, MartS). Further support came from the German Cancer AID (DKH 70113869 to PL, CP). JW was supported by the Helmholtz International Graduate School for Cancer Research in Heidelberg. The funding bodies had no role in the design of the study, nor in the collection, analysis, and interpretation of data, nor in writing the manuscript.
Publisher Copyright:
© 2020 The Author(s).
PY - 2020/3/18
Y1 - 2020/3/18
N2 - 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.
AB - 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.
KW - Cell-of-origin
KW - Chronic lymphocytic leukemia
KW - DNA methylation
KW - T cell antigens
UR - http://www.scopus.com/inward/record.url?scp=85082002085&partnerID=8YFLogxK
U2 - 10.1186/s13073-020-00724-7
DO - 10.1186/s13073-020-00724-7
M3 - Article
C2 - 32188505
AN - SCOPUS:85082002085
SN - 1756-994X
VL - 12
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 29
ER -