IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening
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 >2800 unique compounds, we found...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
May 15 2025
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| In: |
Blood
Year: 2025, Jahrgang: 145, Heft: 20, Pages: 2336-2352 |
| ISSN: | 1528-0020 |
| DOI: | 10.1182/blood.2024027171 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2024027171
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| Verfasserangaben: | Marcel Fabian Pohly, Kerstin Putzker, Sebastian Scheinost, Lena Ben Taarit, Tatjana Walther, Sandra Kummer, Tobias Wertheimer, Minqi Lin, Thi Huong Lan Do, Kristina Handler, Jan Michler, Jarno Kivioja, Karsten Bach, Samanta Kisele, James Kim, Sascha Dietrich, Beat Bornhauser, Wendy Wei-Lynn Wong, Burkhard Becher, Andreas Moor, Joe Lewis, Xenia Ficht, Junyan Lu, Wolfgang Huber, Thorsten Zenz |
MARC
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| 520 | |a 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 >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 α (TNF-α)/NF-κB signaling pathways (birinapant) in T-PLL cells. Focusing on birinapant for its potential in drug repurposing, we uncovered that IAP inhibitor-induced cell death was primarily necroptotic and dependent on TNF-α. 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 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. | ||
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| 700 | 1 | |a Scheinost, Sebastian |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ben Taarit, Lena |e VerfasserIn |4 aut | |
| 700 | 1 | |a Walther, Tatjana |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Lin, Minqi |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Huber, Wolfgang |e VerfasserIn |4 aut | |
| 700 | 1 | |a Zenz, Thorsten |e VerfasserIn |4 aut | |
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