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

Standard

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, Jahrgang 12, Nr. 1, 27.09.2021, S. 5655.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Carlet, M, Völse, K, Vergalli, J, Becker, M, Herold, T, Arner, A, Senft, D, Jurinovic, V, Liu, W-H, 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 2021, 'In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets', NAT COMMUN, Jg. 12, Nr. 1, S. 5655. https://doi.org/10.1038/s41467-021-25963-z

APA

Carlet, M., Völse, K., Vergalli, J., Becker, M., Herold, T., Arner, A., Senft, D., Jurinovic, V., Liu, W-H., Gao, Y., Dill, V., Fehse, B., Baldus, C. D., Bastian, L., Lenk, L., Schewe, D. M., Bagnoli, J. W., Vick, B., Schmid, J. P., ... Jeremias, I. (2021). In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets. NAT COMMUN, 12(1), 5655. https://doi.org/10.1038/s41467-021-25963-z

Vancouver

Carlet M, Völse K, Vergalli J, Becker M, Herold T, Arner A et al. In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets. NAT COMMUN. 2021 Sep 27;12(1):5655. https://doi.org/10.1038/s41467-021-25963-z

Bibtex

@article{adb9968c02034cb284037f3c554cde8d,
title = "In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets",
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.",
author = "Michela Carlet and Kerstin V{\"o}lse and Jenny Vergalli and Martin Becker and Tobias Herold and Anja Arner and Daniela Senft and Vindi Jurinovic and Wen-Hsin Liu and Yuqiao Gao and Veronika Dill and Boris Fehse and Baldus, {Claudia D} and Lorenz Bastian and Lennart Lenk and Schewe, {Denis M} and Bagnoli, {Johannes W} and Binje Vick and Schmid, {Jan Philipp} and Alexander Wilhelm and Rolf Marschalek and Jost, {Philipp J} and Cornelius Miething and Kristoffer Riecken and Marc Schmidt-Supprian and Vera Binder and Irmela Jeremias",
note = "{\textcopyright} 2021. The Author(s).",
year = "2021",
month = sep,
day = "27",
doi = "10.1038/s41467-021-25963-z",
language = "English",
volume = "12",
pages = "5655",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

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 -