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 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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Journal
Blood
Published
2025-01-27
DOI
https://doi.org/10.1182/blood.2024027171
Citations
1
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
1.63
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article

IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening

Thorsten Zenz, Xenia Ficht, Tobias Wertheimer, Beat Bornhäuser et al.
1 citations
Blood
Chronic Lymphocytic Leukemia Research
1.63
article

IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening

Thorsten Zenz, Xenia Ficht, Tobias Wertheimer, Beat Bornhäuser, Thi Huong Lan, Karsten Bach, Jan Michler, Wolfgang K. Huber, Kerstin Putzker, W. Wei‐Lynn Wong, Joe Lewis, Andreas E. Moor, Burkhard Becher, Sebastian Scheinost, Jarno Kivioja, Kristina Handler, Sandra Kummer, Junyan Lu, Marcel Pohly, Samanta Kisele, Tatjana Walther, James Kim, Minqi Lin, Sascha Dietrich, Lena Ben Taarit
article en
1 citations

Abstract

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.

BloodVol. 145(20)
European Molecular Biology Organization (DE), University of Zurich (CH), Heidelberg University (DE), University Hospital Heidelberg (DE), ETH Zurich (CH), Düsseldorf University Hospital (DE), University Hospital of Zurich (CH), National Center for Tumor Diseases (DE), Affimed Therapeutics (Germany) (DE), Life Science Zurich (CH), University Children's Hospital Zurich (CH), Intermolecular (United States) (US), European Molecular Biology Laboratory (DE), DKFZ-ZMBH Alliance (DE), Heinrich Heine University Düsseldorf (DE), Heidelberg University (US)
Good health and well-being
Openalex Percentile: Top 21%
Chronic Lymphocytic Leukemia Research
1.63
DOISourceOpenAlex
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