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

Autor: Carlet M; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Völse K; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Vergalli J; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Becker M; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Herold T; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany.; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partnering Site Munich, Munich, Germany., Arner A; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University (LMU), Munich, Germany., Senft D; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Jurinovic V; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany.; Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University (LMU), Munich, Germany., Liu WH; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Gao Y; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Dill V; Clinic and Policlinic for Internal Medicine III, Technical University of Munich, School of Medicine, Munich, Germany., Fehse B; Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Baldus CD; Internal Medicine II, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany., Bastian L; Internal Medicine II, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany., Lenk L; Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany., Schewe DM; Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany., Bagnoli JW; Anthropology and Human Genomics, Faculty of Biology, Ludwig Maximilian University (LMU), Munich, Germany., Vick B; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany.; German Cancer Consortium (DKTK), Partnering Site Munich, Munich, Germany., Schmid JP; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Wilhelm A; Institute of Pharmaceutical Biology, Diagnosic Center of Acute Leukemias (DCAL), Goethe-University, Frankfurt/Main, Germany., Marschalek R; Institute of Pharmaceutical Biology, Diagnosic Center of Acute Leukemias (DCAL), Goethe-University, Frankfurt/Main, Germany., Jost PJ; German Cancer Consortium (DKTK), Partnering Site Munich, Munich, Germany.; Clinic and Policlinic for Internal Medicine III, Technical University of Munich, School of Medicine, Munich, Germany.; Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Miething C; Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.; German Cancer Consortium (DKTK), Partnering Site Freiburg, Freiburg, Germany., Riecken K; Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Schmidt-Supprian M; Institute of Experimental Hematology, Technical University of Munich, Munich, Germany., Binder V; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University (LMU), Munich, Germany., Jeremias I; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany. Irmela.Jeremias@helmholtz-muenchen.de.; German Cancer Consortium (DKTK), Partnering Site Munich, Munich, Germany. Irmela.Jeremias@helmholtz-muenchen.de.; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University (LMU), Munich, Germany. Irmela.Jeremias@helmholtz-muenchen.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Sep 27; Vol. 12 (1), pp. 5655. Date of Electronic Publication: 2021 Sep 27.
DOI: 10.1038/s41467-021-25963-z
Abstrakt: 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-ER T2 -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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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