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@ARTICLE{Pohly:298340,
      author       = {M. F. Pohly and K. Putzker$^*$ and S. Scheinost and L. Ben
                      Taarit and T. Walther$^*$ and S. Kummer and T. Wertheimer
                      and M. Lin and T. H. L. Do and K. Handler and J. Michler and
                      J. Kivioja and K. Bach and S. Kisele and J. Kim and S.
                      Dietrich and B. Bornhauser and W. W. Wong and B. Becher and
                      A. Moor and J. D. Lewis and X. M. Ficht and J. Lu and W.
                      Huber and T. Zenz},
      title        = {{IAP} dependency of {T}-cell prolymphocytic leukemia
                      identified by high-throughput drug screening.},
      journal      = {Blood},
      volume       = {145},
      number       = {20},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2025-00244},
      pages        = {2336-2352},
      year         = {2025},
      note         = {2025 May 15;145(20):2336-2352},
      abstract     = {T-cell prolymphocytic leukemia (T-PLL) is an aggressive
                      lymphoid malignancy with limited treatment options. To
                      discover new treatment targets for T-PLL, we performed
                      high-throughput drug sensitivity screening on 30 primary
                      patient samples ex-vivo. After screening over 2'800 unique
                      compounds, we found T-PLL to be more resistant to most drug
                      classes, including chemotherapeutics, compared to other
                      blood cancers. Furthermore, we discovered previously not
                      reported vulnerabilities of T-PLL. T-PLL cells exhibited a
                      particular sensitivity to drugs targeting autophagy
                      (thapsigargin, bafilomycin A1), nuclear export (selinexor),
                      and inhibitor of apoptosis proteins (IAPs) (birinapant),
                      sensitivities that were also shared by other T-cell
                      malignancies. Through bulk and single-cell RNA-Sequencing we
                      found these compounds to activate the toll-like-receptor
                      (TLR) (bafilomycin A1), p53 (selinexor), and TNF-ɑ/NFκB
                      signaling pathways (birinapant) in T-PLL cells. Focussing on
                      birinapant for its potential in drug repurposing, we
                      uncovered that IAP inhibitor-induced cell death was
                      primarily necroptotic and dependent on TNF-ɑ. Through
                      spectral flow cytometry we confirmed the absence of cleaved
                      caspase-3 in IAP inhibitor treated T-PLL cells and show that
                      IAP inhibition reduces the proliferation of T-PLL cells
                      stimulated ex-vivo, while showing only a limited effect on
                      non-malignant T-cells. In summary, our study maps the drug
                      sensitivity of T-PLL across a broad range of targets and
                      identifies new therapeutic approaches for T-PLL by targeting
                      IAPs, XPO1 and autophagy, highlighting potential candidates
                      for drug repurposing and novel treatment strategies.},
      cin          = {W040 / B340},
      ddc          = {610},
      cid          = {I:(DE-He78)W040-20160331 / I:(DE-He78)B340-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39869826},
      doi          = {10.1182/blood.2024027171},
      url          = {https://inrepo02.dkfz.de/record/298340},
}