%0 Journal Article
%A Pohly, Marcel F
%A Putzker, Kerstin
%A Scheinost, Sebastian
%A Ben Taarit, Lena
%A Walther, Tatjana
%A Kummer, Sandra
%A Wertheimer, Tobias
%A Lin, Minqi
%A Do, Thi Huong Lan
%A Handler, Kristina
%A Michler, Jan
%A Kivioja, Jarno
%A Bach, Karsten
%A Kisele, Samanta
%A Kim, James
%A Dietrich, Sascha
%A Bornhauser, Beat
%A Wong, Wendy Wei-Lynn
%A Becher, Burkhard
%A Moor, Andreas
%A Lewis, Joe David
%A Ficht, Xenia Maria
%A Lu, Junyan
%A Huber, Wolfgang
%A Zenz, Thorsten
%T IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening.
%J Blood
%V 145
%N 20
%@ 0006-4971
%C Washington, DC
%I American Society of Hematology
%M DKFZ-2025-00244
%P 2336-2352
%D 2025
%Z 2025 May 15;145(20):2336-2352
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39869826
%R 10.1182/blood.2024027171
%U https://inrepo02.dkfz.de/record/298340