TY  - JOUR
AU  - Pohly, Marcel F
AU  - Putzker, Kerstin
AU  - Scheinost, Sebastian
AU  - Ben Taarit, Lena
AU  - Walther, Tatjana
AU  - Kummer, Sandra
AU  - Wertheimer, Tobias
AU  - Lin, Minqi
AU  - Do, Thi Huong Lan
AU  - Handler, Kristina
AU  - Michler, Jan
AU  - Kivioja, Jarno
AU  - Bach, Karsten
AU  - Kisele, Samanta
AU  - Kim, James
AU  - Dietrich, Sascha
AU  - Bornhauser, Beat
AU  - Wong, Wendy Wei-Lynn
AU  - Becher, Burkhard
AU  - Moor, Andreas
AU  - Lewis, Joe David
AU  - Ficht, Xenia Maria
AU  - Lu, Junyan
AU  - Huber, Wolfgang
AU  - Zenz, Thorsten
TI  - IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening.
JO  - Blood
VL  - 145
IS  - 20
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2025-00244
SP  - 2336-2352
PY  - 2025
N1  - 2025 May 15;145(20):2336-2352
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:39869826
DO  - DOI:10.1182/blood.2024027171
UR  - https://inrepo02.dkfz.de/record/298340
ER  -