Michela Carlet, Kerstin Völse, Jenny Vergalli, Martin Becker, Tobias Herold, Anja Arner, Daniela Senft, Vindi Jurinovic, Wen-Hsin Liu, Yuqiao Gao, Veronika Dill, Boris Fehse, Claudia Baldus, Lorenz Bastian, Lennart Lenk, Denis Martin Schewe, Johannes Bagnoli, Binje Vick, Jan Philipp Schmid, Alexander Wilhelm, Rolf Marschalek, Philipp J. Jost, Cornelius Miething, Kristoffer Riecken, Marc Schmidt-Supprian, Vera Binder, Irmela Jeremias
- High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ERT2-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities. The technique identifies a major tumor-maintaining potency of the MLL-AF4 (mixed lineage leukemia, ALL1-fused gene from chromosome 4) fusion, restricted to samples carrying the translocation. DUX4 (double homeobox 4) plays an essential role in patients’ leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.
MetadatenAuthor: | Michela Carlet, Kerstin Völse, Jenny Vergalli, Martin Becker, Tobias HeroldORCiDGND, Anja Arner, Daniela Senft, Vindi Jurinovic, Wen-Hsin Liu, Yuqiao Gao, Veronika Dill, Boris FehseORCiDGND, Claudia BaldusORCiDGND, Lorenz BastianORCiDGND, Lennart Lenk, Denis Martin ScheweORCiDGND, Johannes Bagnoli, Binje VickORCiDGND, Jan Philipp SchmidORCiD, Alexander WilhelmORCiDGND, Rolf MarschalekORCiDGND, Philipp J. Jost, Cornelius MiethingORCiDGND, Kristoffer RieckenORCiDGND, Marc Schmidt-Supprian, Vera Binder, Irmela JeremiasORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-644941 |
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DOI: | https://doi.org/10.1038/s41467-021-25963-z |
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ISSN: | 2041-1723 |
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Parent Title (English): | Nature Communications |
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Publisher: | Nature Publishing Group UK |
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Place of publication: | [London] |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2021/09/27 |
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Date of first Publication: | 2021/09/27 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2022/04/05 |
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Tag: | Cancer models; Genetic engineering; Leukaemia |
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Volume: | 12 |
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Issue: | art. 5655 |
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Page Number: | 11 |
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First Page: | 1 |
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Last Page: | 11 |
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Note: | The work was supported by the Humboldt Postdoctoral Fellowship (to M.C.), and by grants from the European Research Council Consolidator Grant 681524; a Mildred Scheel Professorship by German Cancer Aid; German Research Foundation (D.F.G.); the Collaborative Research Center 1243 “Genetic and Epigenetic Evolution of Hematopoietic Neoplasms”, project A05; DFG proposal MA 1876/13-1; Bettina Bräu Stiftung and Dr. Helmut Legerlotz Stiftung (all to I.J.); by the Joint Funding project “Relapsed ALL” of the German Cancer Consortium (DKTK) (to C.B. and I.J.). T.H. was supported by the Physician Scientists Grant (G-509200-004) from the Helmholtz Zentrum München. P.J.J. was supported by the Max Eder-Program grant from the Deutsche Krebshilfe (program #111738), Deutsche José Carreras Leukämie-Stiftung (DJCLS R 12/22 and DJCLS 21 R/2016), Else Kröner Fresenius Stiftung (2014_A185) and Deutsche Forschungsgemeinschaft (DFG FOR 2036, SFB 1335 and SFB 1371). |
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Note: | Open Access funding enabled and organized by Projekt DEAL. |
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HeBIS-PPN: | 494894105 |
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Institutes: | Biochemie, Chemie und Pharmazie |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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