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| 001 | 142742 | ||
| 005 | 20240229105151.0 | ||
| 024 | 7 | _ | |a 10.1038/leu.2017.252 |2 doi |
| 024 | 7 | _ | |a pmid:28804127 |2 pmid |
| 024 | 7 | _ | |a 0887-6924 |2 ISSN |
| 024 | 7 | _ | |a 1476-5551 |2 ISSN |
| 024 | 7 | _ | |a altmetric:23915761 |2 altmetric |
| 037 | _ | _ | |a DKFZ-2019-00459 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Andersson, E. I. |b 0 |
| 245 | _ | _ | |a Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling. |
| 260 | _ | _ | |a London |c 2018 |b Springer Nature |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1661339942_30652 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing. |
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| 650 | _ | 7 | |a Antineoplastic Agents |2 NLM Chemicals |
| 650 | _ | 7 | |a Biomarkers, Tumor |2 NLM Chemicals |
| 650 | _ | 7 | |a N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide |2 NLM Chemicals |
| 650 | _ | 7 | |a Oxazoles |2 NLM Chemicals |
| 650 | _ | 7 | |a Protein Kinase Inhibitors |2 NLM Chemicals |
| 650 | _ | 7 | |a STAT Transcription Factors |2 NLM Chemicals |
| 650 | _ | 7 | |a Thiazoles |2 NLM Chemicals |
| 650 | _ | 7 | |a Janus Kinases |0 EC 2.7.10.2 |2 NLM Chemicals |
| 700 | 1 | _ | |a Pützer, S. |b 1 |
| 700 | 1 | _ | |a Yadav, B. |b 2 |
| 700 | 1 | _ | |a Dufva, O. |b 3 |
| 700 | 1 | _ | |a Khan, S. |b 4 |
| 700 | 1 | _ | |a He, L. |b 5 |
| 700 | 1 | _ | |a Sellner, Leopold |0 P:(DE-He78)b07a76205b49e86733668b7201520d19 |b 6 |u dkfz |
| 700 | 1 | _ | |a Schrader, A. |b 7 |
| 700 | 1 | _ | |a Crispatzu, G. |b 8 |
| 700 | 1 | _ | |a Oleś, M. |b 9 |
| 700 | 1 | _ | |a Zhang, H. |b 10 |
| 700 | 1 | _ | |a Adnan-Awad, S. |b 11 |
| 700 | 1 | _ | |a Lagström, S. |b 12 |
| 700 | 1 | _ | |a Bellanger, D. |b 13 |
| 700 | 1 | _ | |a Mpindi, J. P. |b 14 |
| 700 | 1 | _ | |a Eldfors, S. |0 0000-0001-5056-4750 |b 15 |
| 700 | 1 | _ | |a Pemovska, T. |b 16 |
| 700 | 1 | _ | |a Pietarinen, P. |b 17 |
| 700 | 1 | _ | |a Lauhio, A. |b 18 |
| 700 | 1 | _ | |a Tomska, K. |0 P:(DE-He78)b19e65a29d89d299cf5a04670a7ff0ae |b 19 |u dkfz |
| 700 | 1 | _ | |a Cuesta-Mateos, C. |b 20 |
| 700 | 1 | _ | |a Faber, E. |b 21 |
| 700 | 1 | _ | |a Koschmieder, S. |b 22 |
| 700 | 1 | _ | |a Brümmendorf, T. H. |b 23 |
| 700 | 1 | _ | |a Kytölä, S. |b 24 |
| 700 | 1 | _ | |a Savolainen, E-R |b 25 |
| 700 | 1 | _ | |a Siitonen, T. |b 26 |
| 700 | 1 | _ | |a Ellonen, P. |b 27 |
| 700 | 1 | _ | |a Kallioniemi, O. |0 0000-0002-3231-0332 |b 28 |
| 700 | 1 | _ | |a Wennerberg, K. |b 29 |
| 700 | 1 | _ | |a Ding, W. |b 30 |
| 700 | 1 | _ | |a Stern, M-H |b 31 |
| 700 | 1 | _ | |a Huber, W. |0 0000-0002-0474-2218 |b 32 |
| 700 | 1 | _ | |a Anders, S. |0 0000-0002-3986-9892 |b 33 |
| 700 | 1 | _ | |a Tang, J. |b 34 |
| 700 | 1 | _ | |a Aittokallio, T. |b 35 |
| 700 | 1 | _ | |a Zenz, T. |0 P:(DE-He78)f3d5f16b49eb47520def635be98d5576 |b 36 |u dkfz |
| 700 | 1 | _ | |a Herling, M. |b 37 |
| 700 | 1 | _ | |a Mustjoki, S. |b 38 |
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