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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Carlet, M; Völse, K; Vergalli, J; Becker, M; Herold, T; Arner, A; Senft, D; Jurinovic, V; Liu, WH; Gao, Y; Dill, V; Fehse, B; Baldus, CD; Bastian, L; Lenk, L; Schewe, DM; Bagnoli, JW; Vick, B; Schmid, JP; Wilhelm, A; Marschalek, R; Jost, PJ; Miething, C; Riecken, K; Schmidt-Supprian, M; Binder, V; Jeremias, I.
In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets.
Nat Commun. 2021; 12(1): 5655 Doi: 10.1038/s41467-021-25963-z [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Co-Autor*innen der Med Uni Graz
Jost Philipp

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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.
Find related publications in this database (using NLM MeSH Indexing)
Adaptor Proteins, Signal Transducing - antagonists & inhibitors, genetics
Adult - administration & dosage
Animals - administration & dosage
Antineoplastic Agents - pharmacology, therapeutic use
Biomarkers, Tumor - antagonists & inhibitors, genetics
Child - administration & dosage
Female - administration & dosage
Gene Silencing - administration & dosage
Homeodomain Proteins - antagonists & inhibitors, genetics
Humans - administration & dosage
Leukemia, Myeloid, Acute - drug therapy, genetics
Male - administration & dosage
Mice - administration & dosage
Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors, genetics
Myeloid-Lymphoid Leukemia Protein - antagonists & inhibitors, genetics
Oncogene Proteins, Fusion - antagonists & inhibitors, genetics
Precision Medicine - methods
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy, genetics
Reverse Genetics - methods
Xenograft Model Antitumor Assays - administration & dosage

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