In vivo inducible reverse genetics in patients’ tumors to identify individual therapeutic targets

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 D. Baldus, Lorenz Bastian, Lennart Lenk, Denis M. Schewe, Johannes W. Bagnoli, Binje Vick, Jan Philipp Schmid, Alexander Wilhelm, Rolf Marschalek, Philipp J. Jost, Cornelius Miething, Kristoffer Riecken, Marc Schmidt-Supprian, Vera Binder and Irmela Jeremias ()
Additional contact information
Michela Carlet: German Research Center for Environmental Health (HMGU)
Kerstin Völse: German Research Center for Environmental Health (HMGU)
Jenny Vergalli: German Research Center for Environmental Health (HMGU)
Martin Becker: German Research Center for Environmental Health (HMGU)
Tobias Herold: German Research Center for Environmental Health (HMGU)
Anja Arner: University Hospital, Ludwig Maximilian University (LMU)
Daniela Senft: German Research Center for Environmental Health (HMGU)
Vindi Jurinovic: German Research Center for Environmental Health (HMGU)
Wen-Hsin Liu: German Research Center for Environmental Health (HMGU)
Yuqiao Gao: German Research Center for Environmental Health (HMGU)
Veronika Dill: Technical University of Munich, School of Medicine
Boris Fehse: University Medical Center Hamburg-Eppendorf
Claudia D. Baldus: Internal Medicine II, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Campus Kiel
Lorenz Bastian: Internal Medicine II, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Campus Kiel
Lennart Lenk: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Denis M. Schewe: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Johannes W. Bagnoli: Anthropology and Human Genomics, Faculty of Biology, Ludwig Maximilian University (LMU)
Binje Vick: German Research Center for Environmental Health (HMGU)
Jan Philipp Schmid: German Research Center for Environmental Health (HMGU)
Alexander Wilhelm: Institute of Pharmaceutical Biology, Diagnosic Center of Acute Leukemias (DCAL), Goethe-University
Rolf Marschalek: Institute of Pharmaceutical Biology, Diagnosic Center of Acute Leukemias (DCAL), Goethe-University
Philipp J. Jost: German Cancer Consortium (DKTK), Partnering Site Munich
Cornelius Miething: Faculty of Medicine
Kristoffer Riecken: University Medical Center Hamburg-Eppendorf
Marc Schmidt-Supprian: Institute of Experimental Hematology, Technical University of Munich
Vera Binder: University Hospital, Ludwig Maximilian University (LMU)
Irmela Jeremias: German Research Center for Environmental Health (HMGU)

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25963-z

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