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Baboon envelope pseudotyped lentiviral vectors: a highly efficient new tool to genetically manipulate T-cell acute lymphoblastic leukaemia-initiating cells

Leukemia volume 31, pages 977–980 (2017)Cite this article

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To investigate this possibility, we next transduced seven different primary T-ALL samples (Supplementary Table 1, UPN525, UPN534, UPN584, UPN633, UPN613, UPN727, UPN763) with LVs carrying a GFP transgene and pseudotyped with chimeric VSVG, H/F or BaEV glycoproteins, which have been previously described.4, 5, 6 Even when used at low multiplicities of infection (MOI=10), H/F and BaEV-LVs respectively transduced 21.6±3.1 and 40.9±7.1% of the leukemic blasts, significantly outperforming the VSVG-LVs (Figures 1d and e and Supplementary Figure 3). These transduction rates reflected stable GFP expression from an integrated proviral DNA, since the GFP fluorescent intensities increased from day 2 to day 6 post-transduction, whereas the percentage of GFP+ blasts remained stable (Supplementary figures 4A and B). In agreement with this, we observed a dose-dependent increase in vector copy numbers coinciding with increasing MOIs and transduction rates (Supplementary Figures 4C and D).

In summary, our data demonstrate that BaEV-pseudotyped LVs have an exceptional capacity to transduce T-ALL LICs without altering their self-renewing properties. This superior transduction efficiency most likely relies on ASCT1/ASCT2 broad expression pattern. Since these BaEV-entry receptors are expressed in T-ALL cells irrespective of their stage of maturation arrest or genomic abnormalities, BaEV-LVs proof to be excellent tools to genetically manipulate all T-ALL subtypes. In this respect, they may have a broader spectrum of application compared with previous vectors,14 whose performance relies on Notch-mediated up-regulation of IL7Rα and thus most likely depends on the NOTCH1/FBXW7 mutational status of the leukemic blasts. In addition to efficiently transducing the leukemic blasts, BaEV LVs did not impact LICs self-renewal capacity, an essential pre-requisite to functionally investigate the molecular pathways involved in T-ALL initiation and development. Furthermore, as integrase-defective LVs are important tools for genome editing protocols,15 our BaEV-pseudotyped LVs are likely to facilitate the development of genomic editing strategies for primary T-ALL cells. BaEV-LVs are thus excellent tools to genetically manipulate LICs and thus identify novel molecular pathways involved in their self-renewal.

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Acknowledgements

This work has been supported by ‘Fondation de France’ to MT and by AFM, ARC and E-rare EC grants to EV.

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Author notes

  1. C Costa, G Hypolite and O Bernadin: These authors contributed equally to this work.

  2. E Verhoeyen and M Tesio: These authors contributed equally to this work.

Authors and Affiliations

  1. CIRI—International Center for Infectiology Research, Université de Lyon, Inserm, U1111,

    C Costa

  2. CNRS, UMR5308,

    C Costa

  3. Ecole Normale Supérieure de Lyon, Université Lyon 1, Lyon, France

    C Costa

  4. Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants Malades, Paris, France

    G Hypolite, V Asnafi, E Macintyre & M Tesio

  5. CIRI–International Center for Infectiology Research, Team EVIR, Université de Lyon, Inserm, U1111,

    O Bernadin, C Lévy, F-L Cosset & E Verhoeyen

  6. Ecole Normale Supérieure de Lyon, Université Lyon 1, Lyon, France

    O Bernadin, C Lévy, F-L Cosset & E Verhoeyen

  7. Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe ‘contrôle métabolique des morts cellulaires’, Nice, France

    E Verhoeyen

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  1. C Costa
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Corresponding author

Correspondence to M Tesio.

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Costa, C., Hypolite, G., Bernadin, O. et al. Baboon envelope pseudotyped lentiviral vectors: a highly efficient new tool to genetically manipulate T-cell acute lymphoblastic leukaemia-initiating cells. Leukemia 31, 977–980 (2017). https://doi.org/10.1038/leu.2016.372

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