title: Gene-expression signatures differ between different clinical forms of familial hemophagocytic lymphohistiocytosis.
abstract: We performed gene-expression profiling of PBMCs obtained from patients with familial hemophagocytic lymphohistiocytosis (FHL) to screen for biologic correlates with the genetic and/or clinical forms of this disease. Unsupervised hierarchical clustering of 167 differentially expressed probe sets, representing 143 genes, identified 3 groups of patients corresponding to the genetic forms and clinical presentations of the disease. Two clusters of up- and down-regulated genes separated patients with perforin-deficient FHL from those with unidentified genetic cause(s) of the disease. The clusterscomprised genes involved in defense/immune responses, apoptosis, zinc homeostasis, and systemic inflammation. Unsupervised hierarchical clustering partitioned patients with unknown genetic cause(s) of FHL into 2 well-distinguished subgroups. Patterns of up- and down-regulated genes separated patients with “late-onset” and “relapsing” forms of FHL from patients with an “early onset and rapidly evolving” form of the disease. A cluster was identified in patients with “late onset and relapsing” form of FHL related to B- and T-cell differentiation/survival, T-cell activation, and vesicular transport. The resulting data suggest that unique gene-expression signatures can distinguish between genetic and clinical subtypes of FHL. These differentially expressed genes may represent biomarkers that can be used as predictors of disease progression.
authors.affiliation: Divisions of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Children’s Hospital Medical Center, University of Cincinnati Faculty of Medicine, Cincinnati, OH 45229, USA. janos.sumegi@cchmc.org
authors.forename: Janos
authors.initials: J
authors.lastname: Sumegi
authors.forename: Shawnagay V
authors.initials: SV
authors.lastname: Nestheide
authors.forename: Michael G
authors.initials: MG
authors.lastname: Barnes
authors.forename: Joyce
authors.initials: J
authors.lastname: Villanueva
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Grom
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Filipovich
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000145:classification / Q000235:genetics* / Q000276:immunology; D005810:Multigene Family; D009154:Mutation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin