In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets
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In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets. / Carlet, Michela; Völse, Kerstin; Vergalli, Jenny; Becker, Martin; Herold, Tobias; Arner, Anja; Senft, Daniela; Jurinovic, Vindi; Liu, Wen-Hsin; Gao, Yuqiao; Dill, Veronika; Fehse, Boris; Baldus, Claudia D; Bastian, Lorenz; Lenk, Lennart; Schewe, Denis M; Bagnoli, Johannes W; Vick, Binje; Schmid, Jan Philipp; Wilhelm, Alexander; Marschalek, Rolf; Jost, Philipp J; Miething, Cornelius; Riecken, Kristoffer; Schmidt-Supprian, Marc; Binder, Vera; Jeremias, Irmela.
In: NAT COMMUN, Vol. 12, No. 1, 27.09.2021, p. 5655.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets
AU - Carlet, Michela
AU - Völse, Kerstin
AU - Vergalli, Jenny
AU - Becker, Martin
AU - Herold, Tobias
AU - Arner, Anja
AU - Senft, Daniela
AU - Jurinovic, Vindi
AU - Liu, Wen-Hsin
AU - Gao, Yuqiao
AU - Dill, Veronika
AU - Fehse, Boris
AU - Baldus, Claudia D
AU - Bastian, Lorenz
AU - Lenk, Lennart
AU - Schewe, Denis M
AU - Bagnoli, Johannes W
AU - Vick, Binje
AU - Schmid, Jan Philipp
AU - Wilhelm, Alexander
AU - Marschalek, Rolf
AU - Jost, Philipp J
AU - Miething, Cornelius
AU - Riecken, Kristoffer
AU - Schmidt-Supprian, Marc
AU - Binder, Vera
AU - Jeremias, Irmela
N1 - © 2021. The Author(s).
PY - 2021/9/27
Y1 - 2021/9/27
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.
AB - 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.
U2 - 10.1038/s41467-021-25963-z
DO - 10.1038/s41467-021-25963-z
M3 - SCORING: Journal article
C2 - 34580292
VL - 12
SP - 5655
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -