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000154170 1001_ $$0P:(DE-He78)fd7de20653a8cbc8aee25717fa667280$$aWierzbinska, Justyna Anna$$b0$$eFirst author
000154170 245__ $$aMethylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL.
000154170 260__ $$aLondon$$bBioMed Central$$c2020
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000154170 520__ $$aIn 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.
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000154170 7001_ $$0P:(DE-He78)cd2ec3f2ae9b2178f113e0f2ed15fc48$$aToth, Reka$$b1
000154170 7001_ $$0P:(DE-He78)4096eeffdfc73b75e8ba63dc621a017d$$aIshaque, Naveed$$b2
000154170 7001_ $$0P:(DE-He78)94de5f7413279464b6e738d91dfae1eb$$aRippe, Karsten$$b3
000154170 7001_ $$0P:(DE-He78)697cb039ca08f3b7e5a2a52dbf020b46$$aMallm, Jan-Philipp$$b4
000154170 7001_ $$0P:(DE-He78)dd57fd8197d9c5e0290f104db294e019$$aKlett, Lara C$$b5
000154170 7001_ $$0P:(DE-He78)833c06a995d272b78f3a20df3eba6e9e$$aMertens, Daniel$$b6
000154170 7001_ $$0P:(DE-He78)f3d5f16b49eb47520def635be98d5576$$aZenz, Thorsten$$b7
000154170 7001_ $$0P:(DE-He78)743a4a82daab55306a2c88b9f6bf8c2f$$aHielscher, Thomas$$b8
000154170 7001_ $$aSeifert, Marc$$b9
000154170 7001_ $$aKüppers, Ralf$$b10
000154170 7001_ $$0P:(DE-He78)45a6854ecf41ba2e65ca3ba0d560f14c$$aAssenov, Yassen$$b11
000154170 7001_ $$0P:(DE-He78)ff1677c63392be9b31a1c8d23db7c9dc$$aLutsik, Pavlo$$b12
000154170 7001_ $$aStilgenbauer, Stephan$$b13
000154170 7001_ $$0P:(DE-HGF)0$$aRoessner, Philipp M$$b14
000154170 7001_ $$0P:(DE-He78)e67f907703fcb2cf909f4d72d50268b5$$aSeiffert, Martina$$b15
000154170 7001_ $$aByrd, John$$b16
000154170 7001_ $$aOakes, Christopher C$$b17
000154170 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b18$$eLast author
000154170 7001_ $$0P:(DE-He78)c403a040c97f91902a7d31b93859f9fc$$aLipka, Daniel$$b19$$eLast author
000154170 773__ $$0PERI:(DE-600)2484394-5$$a10.1186/s13073-020-00724-7$$gVol. 12, no. 1, p. 29$$n1$$p29$$tGenome medicine$$v12$$x1756-994X$$y2020
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