title: Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention.
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.
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, the University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle WA 98101, USA.
authors.forename: Scott N
authors.initials: SN
authors.lastname: Furlan
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Watkins
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, the University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle WA 98101, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Tkachev
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cooley
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Karnail
authors.initials: K
authors.lastname: Singh
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Giver
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamby
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Stempora
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Aneesah
authors.initials: A
authors.lastname: Garrett
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, the University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle WA 98101, USA.
authors.forename: Jingyang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, the University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle WA 98101, USA.
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Betz
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Carly G K
authors.initials: CG
authors.lastname: Ziegler
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Tharp
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Daniel E L
authors.initials: DE
authors.lastname: Promislow
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, the University of Washington, and the Fred Hutchinson Cancer Research Center, Seattle WA 98101, USA. leslie.kean@seattlechildrens.org.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kean
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D059467:Transcriptome
chemical_list: D064096:Aurora Kinase A; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate