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The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development

Oncogene volume 35, pages 2842–2851 (2016)Cite this article

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A Corrigendum to this article was published on 02 June 2016

This article has been updated

Abstract

Graft versus host disease (GvHD), which is the primary complication of allogeneic bone marrow transplantation, can alter the intestinal barrier targeted by activated donor T-cells. Chemical inhibition of the stress protein HSP90 was demonstrated in vitro to inhibit T-cell activation and to modulate endoplasmic reticulum (ER) stress to which intestinal cells are highly susceptible. Since the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17AAG) is developed in clinics, we explored here its ability to control intestinal acute GvHD in vivo in two mouse GvHD models (C57BL/6→BALB/c and FVB/N→Lgr5-eGFP), ex vivo in intestine organoids and in vitro in intestinal epithelial cultures. We show that 17AAG decreases GvHD-associated mortality without impairing graft versus leukemia effect. While 17AAG effect in T-cell activation is just moderate at the dose used in vivo, we observe a striking intestinal integrity protection. At the intestine level, the drug promotes the splicing of the transcription factor X-box binding protein 1 (XBP1), which is a key component of the ER stress. This effect is associated with a decrease in intestinal damage and an increase in Lgr5+ stem cells, Paneth cells and defensins production. The importance of XBP1 splicing control is further confirmed in cultured cells and organoids of primary intestinal epithelium where XBP1 is either shRNA depleted or inhibited with toyocamycin. In conclusion, 17AAG has a protective effect on the epithelial intestinal barrier in mouse models of acute GvHD. This compound deserves to be tested in the therapeutic control of acute GvHD.

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Change history

  • 02 June 2016

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

Abbreviations

17AAG:

17-allylamino-demethoxygeldanamycin

ER:

endoplasmic reticulum

GvHD:

graft versus host disease

GvL:

graft versus leukemia

HSP:

heat shock protein

IEC:

intestinal epithelial cell

ISC:

intestinal stem cell

UPR:

unfolded protein response

XBP1:

X-box binding protein 1

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Acknowledgements

We thank J Haiech (University of Strasbourg), P Saas and B Gaugler (INSERM U1098, Besançon, France), for helpful discussions. We thank P Saas, H Clevers (Hubrecht Institute, The Netherlands) and A Jevnikar (Ontario, CA) for providing A20-luc cells, Lgr5-eGFP mice and IEC 4-1, respectively, and A Bouchot and JF Merlin (INSERM U866, Dijon, France) for excellent technical assistance. This work was supported by grants from the Institut National du Cancer, Agence Nationale de la Recherche, Ligue Nationale Contre le Cancer (‘Labeled teams’ to CG and ES), the Association pour la Recherche sur le Cancer (labeled team to CG and OD), and FEDER. CG team belongs to the LabEx LipSTIC and GR-Ex. ALJ has a doctoral fellowship from La Ligue Nationale Contre le Cancer and AD by the ‘Conseil Régional de Bourgogne’.

Author information

Author notes

  1. A-L Joly and A Deepti: Co-first authors.

  2. E Kohli and C Garrido: Co-last authors.

Authors and Affiliations

  1. INSERM UMR 866, « Equipe labellisée» Ligue National contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France

    A-L Joly, A Deepti, A Seignez, A Goloudina, S Hebrard, E Schmitt, S Richaud, E Fourmaux, A Hammann, G Jego, O Demidov, E Kohli & C Garrido

  2. Université de Bourgogne, Dijon, France

    A-L Joly, A Deepti, A Seignez, A Goloudina, S Hebrard, E Schmitt, S Richaud, E Fourmaux, A Hammann, G Jego, O Demidov, E Kohli & C Garrido

  3. CHU, Dijon, France

    A Seignez

  4. INSERM, UMR S938, Centre de Recherche Saint-Antoine, Paris, France

    A Collura & M Svrcek

  5. INSERM U748, Institut de Virologie, Strasbourg, France

    E Robinet

  6. Institut Hospitalo-Universitaire de Strasbourg, Strasbourg, France

    E Robinet

  7. INSERM UMR1009, Institut Gustave Roussy, Villejuif, France

    E Solary

  8. Université Paris-Sud 11, Villejuif, France

    E Solary

  9. Anticancer Centre George François Leclerc, Dijon, France

    C Garrido

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Correspondence to C Garrido.

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Joly, AL., Deepti, A., Seignez, A. et al. The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development. Oncogene 35, 2842–2851 (2016). https://doi.org/10.1038/onc.2015.242

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