{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T23:18:38Z","timestamp":1793056718498,"version":"4.5.0"},"reference-count":46,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,5,15]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u00a0vivo. After screening &amp;gt;2800 unique compounds, we found T-PLL to be more resistant to most drug classes, including chemotherapeutics, than other blood cancers. Furthermore, we discovered previously unreported vulnerabilities of T-PLL. T-PLL cells exhibited a particular sensitivity to drugs targeting autophagy (thapsigargin and 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 (bafilomycin A1), p53 (selinexor), and tumor necrosis factor \u03b1 (TNF-\u03b1)\/NF-\u03baB signaling pathways (birinapant) in T-PLL cells. Focusing on birinapant for its potential in drug repurposing, we uncovered that IAP inhibitor\u2013induced cell death was primarily necroptotic and dependent on TNF-\u03b1. Through spectral flow cytometry, we confirmed the absence of cleaved caspase-3 in IAP inhibitor\u2013treated T-PLL cells and show that IAP inhibition reduces the proliferation of T-PLL cells stimulated ex\u00a0vivo, while showing only a limited effect on nonmalignant 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, exportin 1, and autophagy, highlighting potential candidates for drug repurposing and novel treatment strategies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024027171","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T20:58:53Z","timestamp":1738011533000},"page":"2336-2352","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":3,"title":["IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0393-5840","authenticated-orcid":false,"given":"Marcel Fabian","family":"Pohly","sequence":"first","affiliation":[{"name":"1Department of Medical Oncology and Hematology, University Hospital and University 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