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

Scott N. Furlan, Benjamin Watkins, Victor Tkachev, Ryan Flynn, Sarah Cooley, Swetha Ramakrishnan, Karnail Singh, Cindy Giver, Kelly Hamby, Linda Stempora, Aneesah Garrett, Jingyang Chen, Kayla M. Betz, Carly G K Ziegler, Gregory K. Tharp, Steven E. Bosinger, Daniel E L Promislow, Jeffrey S. Miller, Edmund K. Waller, Bruce R. BlazarLeslie S. Kean

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Article number3231
JournalScience Translational Medicine
Volume7
Issue number315
DOIs
StatePublished - Nov 25 2015

Bibliographical note

Funding Information:
We gratefully acknowledge the technical assistance of N. Kozyr and the veterinary care provided by E. Strobert, J. Jenkins, A. Torrence, K. Vogel, and J. Lewellen, in addition to the services provided by both the Vanderbilt Technologies for Advanced Genomics and the OHSU Gene Profiling Shared Resource. 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 NIH (grant P51 OD 010425). Funding was also provided through Emory University Atlanta Clinical and Translational Science Institute Pilot Grant (to E.K.W.), the NIH (2 R01 HL56067, R01 AI 34495, and P01 AI 056299; to B.R.B.), and the National Heart, Lung, and Blood Institute (5 R01 HL095791) and the National Institute of Allergy and Infectious Diseases (5U19-AI051731; to L.S.K.).

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