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000298340 1001_ $$00000-0003-0393-5840$$aPohly, Marcel F$$b0
000298340 245__ $$aIAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening.
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000298340 500__ $$a2025 May 15;145(20):2336-2352
000298340 520__ $$aT-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.
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000298340 7001_ $$0P:(DE-He78)04eb74f47fce0fa7e60ef3880ee01ada$$aPutzker, Kerstin$$b1$$udkfz
000298340 7001_ $$aScheinost, Sebastian$$b2
000298340 7001_ $$aBen Taarit, Lena$$b3
000298340 7001_ $$0P:(DE-He78)e8feda17d03b95bda3e8717e79dc07b8$$aWalther, Tatjana$$b4$$udkfz
000298340 7001_ $$aKummer, Sandra$$b5
000298340 7001_ $$00000-0002-8480-7391$$aWertheimer, Tobias$$b6
000298340 7001_ $$aLin, Minqi$$b7
000298340 7001_ $$00000-0001-8058-4410$$aDo, Thi Huong Lan$$b8
000298340 7001_ $$00000-0001-8952-6487$$aHandler, Kristina$$b9
000298340 7001_ $$aMichler, Jan$$b10
000298340 7001_ $$00000-0002-4046-0963$$aKivioja, Jarno$$b11
000298340 7001_ $$00000-0003-3622-1115$$aBach, Karsten$$b12
000298340 7001_ $$00000-0003-0369-7854$$aKisele, Samanta$$b13
000298340 7001_ $$aKim, James$$b14
000298340 7001_ $$aDietrich, Sascha$$b15
000298340 7001_ $$00000-0003-2890-3191$$aBornhauser, Beat$$b16
000298340 7001_ $$00000-0003-3155-1211$$aWong, Wendy Wei-Lynn$$b17
000298340 7001_ $$00000-0002-1541-7867$$aBecher, Burkhard$$b18
000298340 7001_ $$00000-0001-8715-8449$$aMoor, Andreas$$b19
000298340 7001_ $$00000-0002-9926-1328$$aLewis, Joe David$$b20
000298340 7001_ $$00000-0002-4534-8225$$aFicht, Xenia Maria$$b21
000298340 7001_ $$aLu, Junyan$$b22
000298340 7001_ $$aHuber, Wolfgang$$b23
000298340 7001_ $$aZenz, Thorsten$$b24
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