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@ARTICLE{Bhattacharya:126145,
      author       = {N. Bhattacharya and M. Reichenzeller and M.
                      Caudron-Herger$^*$ and S. Haebe and N. R. Brady$^*$ and S.
                      Diener and M. Nothing and H. Döhner and S. Stilgenbauer and
                      K. Rippe$^*$ and D. Mertens$^*$},
      title        = {{L}oss of cooperativity of secreted {CD}40{L} and increased
                      dose-response to {IL}4 on {CLL} cell viability correlates
                      with enhanced activation of {NF}-k{B} and {STAT}6.},
      journal      = {International journal of cancer},
      volume       = {136},
      number       = {1},
      issn         = {0020-7136},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2017-02260},
      pages        = {65 - 73},
      year         = {2015},
      abstract     = {Chronic lymphocytic leukemia (CLL) cells fail to enter
                      apoptosis in vivo as opposed to their non-malignant
                      B-lymphocyte counterparts. The ability of CLL cells to
                      escape apoptosis is highly dependent on their
                      microenvironment. Compared to non-malignant B cells, CLL
                      cells are more responsive to complex stimuli that can be
                      reproduced in vitro by the addition of cytokines. To
                      understand the molecular mechanism of the
                      environment-dependent anti-apoptotic signaling circuitry of
                      CLL cells, we quantified the effect of the SDF-1, BAFF,
                      APRIL, anti-IgM, interleukin-4 (IL4) and secreted CD40L
                      (sCD40L) on the survival of in vitro cultured CLL cells and
                      found IL4 and sCD40L to be most efficient in rescuing CLL
                      cells from apoptosis. In quantitative dose-response
                      experiments using cell survival as readout, the binding
                      affinity of IL4 to its receptor was similar between
                      malignant and non-malignant cells. However, the downstream
                      signaling in terms of the amount of STAT6 and its degree of
                      phosphorylation was highly stimulated in CLL cells. In
                      contrast, the response to sCD40L showed a loss of
                      cooperative binding in CLL cells but displayed a largely
                      increased ligand binding affinity. Although a
                      high-throughput microscopy analysis did not reveal a
                      significant difference in the spatial CD40 receptor
                      organization, the downstream signaling showed an enhanced
                      activation of the NF-kB pathway in the malignant cells.
                      Thus, we propose that the anti-apoptotic phenotype of CLL
                      involves a sensitized response for IL4 dependent STAT6
                      phosphorylation, and an activation of NF-kB signaling due to
                      an increased affinity of sCD40L to its receptor.},
      keywords     = {IL4 protein, human (NLM Chemicals) / NF-kappa B (NLM
                      Chemicals) / STAT6 Transcription Factor (NLM Chemicals) /
                      STAT6 protein, human (NLM Chemicals) / CD40 Ligand (NLM
                      Chemicals) / Interleukin-4 (NLM Chemicals)},
      cin          = {B170 / B066 / B061},
      ddc          = {610},
      cid          = {I:(DE-He78)B170-20160331 / I:(DE-He78)B066-20160331 /
                      I:(DE-He78)B061-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24828787},
      doi          = {10.1002/ijc.28974},
      url          = {https://inrepo02.dkfz.de/record/126145},
}