IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening
Abstract
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.
Article Details
Authors (25)
Marcel Fabian Pohly
1Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland
Kerstin Putzker
3Chemical Biology Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany
Sebastian Scheinost
4Molecular Therapy in Hematology and Oncology, Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
Lena Ben Taarit
4Molecular Therapy in Hematology and Oncology, Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
Tatjana Walther
4Molecular Therapy in Hematology and Oncology, Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany
Sandra Kummer
1Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland
Tobias Wertheimer
Minqi Lin
5Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Thi Huong Lan Do
1Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland
Kristina Handler
Jan Michler
2Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
Jarno Kivioja
1Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland
Karsten Bach
2Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
Samanta Kisele
James Kim
Sascha Dietrich
Beat Bornhauser
Wendy Wei-Lynn Wong
10Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
Burkhard Becher
Andreas Moor
2Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
Joe Lewis
3Chemical Biology Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany
Xenia Ficht
2Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
Junyan Lu
Wolfgang Huber
Thorsten Zenz