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@ARTICLE{Ziegler:274141,
      author       = {N. Ziegler and M. Cortés-López and F. Alt and M. Sprang
                      and A. Ustjanzew and N. Lehmann and K. El Malki and A.
                      Wingerter and A. Russo and O. Beck and S. Attig and L. Roth
                      and J. König and C. Paret$^*$ and J. Faber$^*$},
      title        = {{A}nalysis of {RBP} expression and binding sites identifies
                      {PTBP}1 as a regulator of {CD}19 expression in {B}-{ALL}.},
      journal      = {OncoImmunology},
      volume       = {12},
      number       = {1},
      issn         = {2162-4011},
      address      = {Abingdon},
      publisher    = {Taylor $\&$ Franics},
      reportid     = {DKFZ-2023-00451},
      pages        = {2184143},
      year         = {2023},
      abstract     = {Despite massive improvements in the treatment of B-ALL
                      through CART-19 immunotherapy, a large number of patients
                      suffer a relapse due to loss of the targeted epitope.
                      Mutations in the CD19 locus and aberrant splicing events are
                      known to account for the absence of surface antigen.
                      However, early molecular determinants suggesting therapy
                      resistance as well as the time point when first signs of
                      epitope loss appear to be detectable are not enlightened so
                      far. By deep sequencing of the CD19 locus, we identified a
                      blast-specific 2-nucleotide deletion in intron 2 that exists
                      in $35\%$ of B-ALL samples at initial diagnosis. This
                      deletion overlaps with the binding site of RNA binding
                      proteins (RBPs) including PTBP1 and might thereby affect
                      CD19 splicing. Moreover, we could identify a number of other
                      RBPs that are predicted to bind to the CD19 locus being
                      deregulated in leukemic blasts, including NONO. Their
                      expression is highly heterogeneous across B-ALL molecular
                      subtypes as shown by analyzing 706 B-ALL samples accessed
                      via the St. Jude Cloud. Mechanistically, we show that
                      downregulation of PTBP1, but not of NONO, in 697 cells
                      reduces CD19 total protein by increasing intron 2 retention.
                      Isoform analysis in patient samples revealed that blasts, at
                      diagnosis, express increased amounts of CD19 intron 2
                      retention compared to normal B cells. Our data suggest that
                      loss of RBP functionality by mutations altering their
                      binding motifs or by deregulated expression might harbor the
                      potential for the disease-associated accumulation of
                      therapy-resistant CD19 isoforms.},
      keywords     = {B-ALL (Other) / CART19 therapy (Other) / CD19 (Other) /
                      CD20 (Other) / NONO (Other) / PTBP1 (Other) / RBP (Other) /
                      isoforms (Other) / splicing (Other)},
      cin          = {FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36875548},
      pmc          = {pmc:PMC9980455},
      doi          = {10.1080/2162402X.2023.2184143},
      url          = {https://inrepo02.dkfz.de/record/274141},
}