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@ARTICLE{Wierzbinska:154170,
      author       = {J. A. Wierzbinska$^*$ and R. Toth$^*$ and N. Ishaque$^*$
                      and K. Rippe$^*$ and J.-P. Mallm$^*$ and L. C. Klett$^*$ and
                      D. Mertens$^*$ and T. Zenz and T. Hielscher$^*$ and M.
                      Seifert and R. Küppers and Y. Assenov$^*$ and P. Lutsik$^*$
                      and S. Stilgenbauer and P. M. Roessner$^*$ and M.
                      Seiffert$^*$ and J. Byrd and C. C. Oakes and C. Plass$^*$
                      and D. Lipka$^*$},
      title        = {{M}ethylome-based cell-of-origin modeling ({M}ethyl-{COOM})
                      identifies aberrant expression of immune regulatory
                      molecules in {CLL}.},
      journal      = {Genome medicine},
      volume       = {12},
      number       = {1},
      issn         = {1756-994X},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2020-00629},
      pages        = {29},
      year         = {2020},
      note         = {Modyfied by adding this comment for testin
                      purposes#EA:B340#LA:B340#},
      abstract     = {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.},
      cin          = {B370 / HD01 / B066 / B061 / C060 / B060 / B340},
      ddc          = {610},
      cid          = {I:(DE-He78)B370-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B066-20160331 / I:(DE-He78)B061-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)B060-20160331 /
                      I:(DE-He78)B340-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32188505},
      doi          = {10.1186/s13073-020-00724-7},
      url          = {https://inrepo02.dkfz.de/record/154170},
}