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

• Published in: Oncogene 2016-06, Vol.35 (22), p.2842-2851
• Main Authors: Joly, A-L, Deepti, A, Seignez, A, Goloudina, A, Hebrard, S, Schmitt, E, Richaud, S, Fourmaux, E, Hammann, A, Collura, A, Svrcek, M, Jego, G, Robinet, E, Solary, E, Demidov, O, Kohli, E, Garrido, C
• Format: Article
• Language: English
• Subjects: 13; 13/51; 59/5; 631/250/1619; 631/67/1990; 631/80/304; 64/60; 82/1; Activating transcription factor 1; Animal models; Animals; Apoptosis; Benzoquinones - pharmacology; Benzoquinones - therapeutic use; Biochemistry, Molecular Biology; Bone marrow; Bone marrow transplantation; Cancer; Care and treatment; Cell activation; Cell Biology; Cell proliferation; Cellular Biology; Coagulation factors; Cytoprotection - drug effects; Defensins; Endoplasmic reticulum; Epithelium; Female; Genetics; Graft versus host disease; Graft versus host reaction; Graft vs Host Disease - drug therapy; Graft vs Host Disease - genetics; Graft vs Host Disease - pathology; Graft vs. host disease; Health aspects; Heat shock proteins; Hematopoietic stem cell transplantation; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 protein; Human Genetics; Internal Medicine; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Intestine; Intestines; Intestines - drug effects; Intestines - pathology; Lactams, Macrocyclic - pharmacology; Lactams, Macrocyclic - therapeutic use; Life Sciences; Lymphocytes T; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Oncology; Organoids; original-article; Paneth cells; Physiological aspects; Prevention; Proteins; RNA Splicing - drug effects; Skin & tissue grafts; Stem Cell Niche - drug effects; Stem cell transplantation; Stem cells; Stress; T cells; Transplants & implants; X-Box Binding Protein 1 - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.242

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.