Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention

• Type of Material: Article
• Authors: Scott N. Furlan, University of Washington; Benjamin Watkins, Emory University; Victor Tkachev, University of Washington; Ryan Flynn, Univ Minnesota; Sarah Cooley, Univ Minnesota; Swetha Ramakrishnan, Emory University; Karnail Singh, Emory University; Cynthia Giver, Emory University; Kelly Hamby, Emory University; Linda Stempora, Emory University; Aneesah Garrett, Emory University; Jingyang Chen, University of Washington; Kayla M. Betz, University of Washington; Carly G.K. Ziegler, Mem Sloan Kettering Canc Ctr; Gregory K. Tharp, Emory University; Steven Bosinger, Emory University; Daniel E.L. Promislow, University of Washington; Jeffrey S. Miller, Univ Minnesota; Edmund Waller, Emory University; Bruce R. Blazar, Univ Minnesota; Leslie Kean, Emory University
• Language: English
• Date: 2015-11-25
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015, American Association for the Advancement of Science.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aad3231
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 7
• Issue: 315
• Start Page: 315ra191
• End Page: 315ra191
• Grant/Funding Information: This work was supported by Yerkes National Primate Research Center Base Grant, #RR00165. Washington National Primate Research Center at the University of Washington support was funded through the Office of Research Infrastructure Programs at the National Institutes of Health, Grant #P51 OD 010425. Funding also provided through Emory University ACTSI Pilot Grant (EKW), NIH 2 R01 HL56067, R01 AI 34495 and P01 AI 056299 (BRB), and NHLBI 5 R01 HL095791, NIAID 5U19-AI051731 (LSK).
• Keywords: Science & Technology; STEM-CELL TRANSPLANTATION; GRAFT-VERSUS-HOST; Life Sciences & Biomedicine; Research & Experimental Medicine; Cell Biology; CD4(+) T-CELLS
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of nonhuman primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3+ T cells from five cohorts: allogeneic transplant recipients receiving (i) no immunoprophylaxis (No Rx), (ii) sirolimus monotherapy (Siro), (iii) tacrolimus-methotrexate (Tac-Mtx), as well as (iv) autologous transplant recipients (Auto) and (v) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for alloreactive T cells and determine the impact of both mTOR (mechanistic target of rapamycin) and calcineurin inhibition on GVHD. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function, and cytokine synthesis. Within these pathways, we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD and suggest that AURKA should be considered a target for preventing GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD.