title: RNA and protein expression of herpesvirus entry mediator (HVEM) is associated with molecular markers, immunity-related pathways and relapse-free survival of patients with AML.
abstract: Immune checkpoint molecules are highly relevant as potential prognostic markers and therapeutic targets in malignant diseases. HVEM belongs to the TNF receptor family and provides stimulatory as well as inhibitory signals depending on the ligand. Abnormal HVEM expression has been described in various malignancies, but the role in AML is unknown. Here we report extensive data on HVEM surface protein expression analyzed by flow cytometry on bone marrow leukemic cells of 169 AML patients at diagnosis. An independent cohort of 512 AML patients was analyzed for HVEM mRNA expression in bone marrow samples by Affymetrix microarrays. Consistently for both cohorts and methods, we show that HVEM was differentially expressed and that expression levels were associated with defined genetic markers. HVEM expression was lower in cases with FLT3-ITD (p = 0.001, p < 0.001), with mutations in NPM1 (p = 0.001, p < 0.001) or with the combination of NPM1 mutation and FLT3 wild type (p = 0.049, p = 0.050), while a biallelic mutation in CEBPA correlated positively with higher HVEM expression (p = 0.015, p < 0.001). In a differential gene expression analysis, we found 13 genes including HOXA9, MEIS1 and MN1 that were closely associated with HVEM expression. Besides, four gene sets closely linked to immunity were enriched in HVEM (high) samples. Finally, high expression of HVEM was associated with a trend toward longer relapse-free survival. The results of this study provide new information on the potential significance of HVEM in AML.
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany. Felix.Lichtenegger@med.uni-muenchen.de.|Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, Munich, Germany. Felix.Lichtenegger@med.uni-muenchen.de.|Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Universität München, Munich, Germany. Felix.Lichtenegger@med.uni-muenchen.de.
authors.forename: Felix S
authors.initials: FS
authors.lastname: Lichtenegger
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Kondla
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Krempasky
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Weber
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Pathogenesis of Acute Leukemia, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Krupka
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Pathogenesis of Acute Leukemia, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Medicine A, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.affiliation: Department of Medicine A, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: German Society of Hematology and Oncology, Berlin, Germany.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Wörmann
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Pathogenesis of Acute Leukemia, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Marchioninistraße 15, 81377, Munich, Germany.|Clinical Cooperation Group Immunotherapy, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Subklewe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001853:Bone Marrow / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D012313:RNA / Q000235:genetics; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics* / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D053240:Receptors, Tumor Necrosis Factor, Member 14; D000090243:Nucleophosmin; D012313:RNA
keywords: Acute myeloid leukemia (AML); Costimulation; Gene expression analysis; Herpesvirus entry mediator (HVEM); Immune checkpoint molecules; Immunophenotyping