TY  - JOUR
A1  - Carlet, Michela
A1  - Völse, Kerstin
A1  - Vergalli, Jenny
A1  - Becker, Martin
A1  - Herold, Tobias
A1  - Arner, Anja
A1  - Senft, Daniela
A1  - Jurinovic, Vindi
A1  - Liu, Wen-Hsin
A1  - Gao, Yuqiao
A1  - Dill, Veronika
A1  - Fehse, Boris
A1  - Baldus, Claudia
A1  - Bastian, Lorenz
A1  - Lenk, Lennart
A1  - Schewe, Denis Martin
A1  - Bagnoli, Johannes
A1  - Vick, Binje
A1  - Schmid, Jan Philipp
A1  - Wilhelm, Alexander
A1  - Marschalek, Rolf
A1  - Jost, Philipp J.
A1  - Miething, Cornelius
A1  - Riecken, Kristoffer
A1  - Schmidt-Supprian, Marc
A1  - Binder, Vera
A1  - Jeremias, Irmela
T1  - In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets
T2  - Nature Communications
N2  - 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.
KW  - Cancer models
KW  - Genetic engineering
KW  - Leukaemia
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/64494
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-644941
SN  - 2041-1723
N1  - 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).
N1  - Open Access funding enabled and organized by Projekt DEAL.
VL  - 12
IS  - art. 5655
SP  - 1
EP  - 11
PB  - Nature Publishing Group UK
CY  - [London]
ER  -