Journal Article

DKFZ-2025-00244

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening.

Pohly, M. F. ; Putzker, K.DKFZ* ; Scheinost, S. ; Ben Taarit, L. ; Walther, T.DKFZ* ; Kummer, S. ; Wertheimer, T. ; Lin, M. ; Do, T. H. L. ; Handler, K. ; Michler, J. ; Kivioja, J. ; Bach, K. ; Kisele, S. ; Kim, J. ; Dietrich, S. ; Bornhauser, B. ; Wong, W. W. ; Becher, B. ; Moor, A. ; Lewis, J. D. ; Ficht, X. M. ; Lu, J. ; Huber, W. ; Zenz, T.

2025
American Society of Hematology Washington, DC

This record in other databases:  

Please use a persistent id in citations: doi:10.1182/blood.2024027171

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 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.

Note: 2025 May 15;145(20):2336-2352

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Contributing Institute(s):

1. Chemische Biologie Core Facility (W040)
2. Translationale Medizinische Onkologie (B340)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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