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Multiple genes surrounding Bcl-xL, a common retroviral insertion site, can influence hematopoiesis individually or in concert

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Multiple genes surrounding Bcl-xL, a common retroviral insertion site, can influence hematopoiesis individually or in concert. / Ha, Teng-Cheong; Stahlhut, Maike; Rothe, Michael; Paul, Gabi; Dziadek, Violetta; Morgan, Michael A; Brugman, Martijn; Fehse, Boris; Kustikova, Olga; Schambach, Axel; Baum, Christopher.

In: HUM GENE THER, Vol. 32, No. 9-10, 05.2021, p. 458-472.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ha, T-C, Stahlhut, M, Rothe, M, Paul, G, Dziadek, V, Morgan, MA, Brugman, M, Fehse, B, Kustikova, O, Schambach, A & Baum, C 2021, 'Multiple genes surrounding Bcl-xL, a common retroviral insertion site, can influence hematopoiesis individually or in concert', HUM GENE THER, vol. 32, no. 9-10, pp. 458-472. https://doi.org/10.1089/hum.2019.344

APA

Ha, T-C., Stahlhut, M., Rothe, M., Paul, G., Dziadek, V., Morgan, M. A., Brugman, M., Fehse, B., Kustikova, O., Schambach, A., & Baum, C. (2021). Multiple genes surrounding Bcl-xL, a common retroviral insertion site, can influence hematopoiesis individually or in concert. HUM GENE THER, 32(9-10), 458-472. https://doi.org/10.1089/hum.2019.344

Vancouver

Ha T-C, Stahlhut M, Rothe M, Paul G, Dziadek V, Morgan MA et al. Multiple genes surrounding Bcl-xL, a common retroviral insertion site, can influence hematopoiesis individually or in concert. HUM GENE THER. 2021 May;32(9-10):458-472. https://doi.org/10.1089/hum.2019.344

Bibtex

@article{42138d4e502b4b4f833191f2928633bf,
title = "Multiple genes surrounding Bcl-xL, a common retroviral insertion site, can influence hematopoiesis individually or in concert",
abstract = "Retroviral insertional mutagenesis (RIM) is both a relevant risk in gene therapy and a powerful tool for identifying genes that enhance the competitiveness of repopulating hematopoietic stem and progenitor cells (HSPCs). However, focusing only on the gene closest to the retroviral vector insertion site (RVIS) may underestimate the effects of RIM, as dysregulation of distal and/or multiple genes by a single insertion event was reported in several studies. As a proof of concept, we examined the common insertion site (CIS) Bcl-xL, which revealed seven genes located within ±150 kb from the RVIS for our study. We confirmed that Bcl-xL enhanced the competitiveness of HSPCs, whereas the Bcl-xL neighbor Id1 hindered HSPC long-term repopulation. This negative influence of Id1 could be counteracted by co-expressing Bcl-xL. Interestingly, >90% of early reconstituted myeloid cells were found to originate from transduced HSPCs upon simultaneous overexpression of Bcl-xL and Id1, which implies that Bcl-xL and Id1 can collaborate to rapidly replenish the myeloid compartment under stress conditions. To directly compare the competitiveness of HSPCs conveyed by multiple transgenes, we developed a multiple competitor competitive repopulation (MCCR) assay to simultaneously screen effects on HSPC repopulating capacity in a single mouse. The MCCR assay revealed that multiple genes within a CIS can have positive or negative impact on hematopoiesis. Furthermore, these data highlight the importance of studying multiple genes located within the proximity of an insertion site to understand complex biological effects, especially as the number of gene therapy patients increases.",
author = "Teng-Cheong Ha and Maike Stahlhut and Michael Rothe and Gabi Paul and Violetta Dziadek and Morgan, {Michael A} and Martijn Brugman and Boris Fehse and Olga Kustikova and Axel Schambach and Christopher Baum",
year = "2021",
month = may,
doi = "10.1089/hum.2019.344",
language = "English",
volume = "32",
pages = "458--472",
journal = "HUM GENE THER",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "9-10",

}

RIS

TY - JOUR

T1 - Multiple genes surrounding Bcl-xL, a common retroviral insertion site, can influence hematopoiesis individually or in concert

AU - Ha, Teng-Cheong

AU - Stahlhut, Maike

AU - Rothe, Michael

AU - Paul, Gabi

AU - Dziadek, Violetta

AU - Morgan, Michael A

AU - Brugman, Martijn

AU - Fehse, Boris

AU - Kustikova, Olga

AU - Schambach, Axel

AU - Baum, Christopher

PY - 2021/5

Y1 - 2021/5

N2 - Retroviral insertional mutagenesis (RIM) is both a relevant risk in gene therapy and a powerful tool for identifying genes that enhance the competitiveness of repopulating hematopoietic stem and progenitor cells (HSPCs). However, focusing only on the gene closest to the retroviral vector insertion site (RVIS) may underestimate the effects of RIM, as dysregulation of distal and/or multiple genes by a single insertion event was reported in several studies. As a proof of concept, we examined the common insertion site (CIS) Bcl-xL, which revealed seven genes located within ±150 kb from the RVIS for our study. We confirmed that Bcl-xL enhanced the competitiveness of HSPCs, whereas the Bcl-xL neighbor Id1 hindered HSPC long-term repopulation. This negative influence of Id1 could be counteracted by co-expressing Bcl-xL. Interestingly, >90% of early reconstituted myeloid cells were found to originate from transduced HSPCs upon simultaneous overexpression of Bcl-xL and Id1, which implies that Bcl-xL and Id1 can collaborate to rapidly replenish the myeloid compartment under stress conditions. To directly compare the competitiveness of HSPCs conveyed by multiple transgenes, we developed a multiple competitor competitive repopulation (MCCR) assay to simultaneously screen effects on HSPC repopulating capacity in a single mouse. The MCCR assay revealed that multiple genes within a CIS can have positive or negative impact on hematopoiesis. Furthermore, these data highlight the importance of studying multiple genes located within the proximity of an insertion site to understand complex biological effects, especially as the number of gene therapy patients increases.

AB - Retroviral insertional mutagenesis (RIM) is both a relevant risk in gene therapy and a powerful tool for identifying genes that enhance the competitiveness of repopulating hematopoietic stem and progenitor cells (HSPCs). However, focusing only on the gene closest to the retroviral vector insertion site (RVIS) may underestimate the effects of RIM, as dysregulation of distal and/or multiple genes by a single insertion event was reported in several studies. As a proof of concept, we examined the common insertion site (CIS) Bcl-xL, which revealed seven genes located within ±150 kb from the RVIS for our study. We confirmed that Bcl-xL enhanced the competitiveness of HSPCs, whereas the Bcl-xL neighbor Id1 hindered HSPC long-term repopulation. This negative influence of Id1 could be counteracted by co-expressing Bcl-xL. Interestingly, >90% of early reconstituted myeloid cells were found to originate from transduced HSPCs upon simultaneous overexpression of Bcl-xL and Id1, which implies that Bcl-xL and Id1 can collaborate to rapidly replenish the myeloid compartment under stress conditions. To directly compare the competitiveness of HSPCs conveyed by multiple transgenes, we developed a multiple competitor competitive repopulation (MCCR) assay to simultaneously screen effects on HSPC repopulating capacity in a single mouse. The MCCR assay revealed that multiple genes within a CIS can have positive or negative impact on hematopoiesis. Furthermore, these data highlight the importance of studying multiple genes located within the proximity of an insertion site to understand complex biological effects, especially as the number of gene therapy patients increases.

U2 - 10.1089/hum.2019.344

DO - 10.1089/hum.2019.344

M3 - SCORING: Journal article

C2 - 33012194

VL - 32

SP - 458

EP - 472

JO - HUM GENE THER

JF - HUM GENE THER

SN - 1043-0342

IS - 9-10

ER -