title: Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition.
abstract: Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3). However, soluble NKG2DL (sNKG2DL) can be released from the cell surface, impairing immune recognition. Here, we examined whether hypomethylating agents modulate the release of sNKG2DL from AML cells. Results demonstrated that AZA- and DAC-treated AML cells reduce the release of sNKG2DL, preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2DL engagement. We show that the shedding of MICA, MICB and ULBP2 is inhibited by the increased expression of TIMP3, an ADAM17 inhibitor, after DAC treatment. The TIMP3 gene is highly methylated in AML cells lines and in AML patients (25.5%), in which it is significantly associated with an adverse cytogenetic prognosis of the disease. Overall, TIMP3 could be a target of the demethylating treatments in AML patients, leading to a decrease in MICA, MICB and ULBP2 shedding and the enhancement of the lytic activity of NK cells through the immune recognition mediated by the NKG2D receptor.
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Aroa Baragaño
authors.initials: AB
authors.lastname: Raneros
authors.affiliation: Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Minguela
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Rodriguez
authors.affiliation: Department of Hematology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Colado
authors.affiliation: Department of Hematology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Bernal
authors.affiliation: Hematology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Department of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Anguita
authors.affiliation: Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Adela Vasco
authors.initials: AV
authors.lastname: Mogorron
authors.affiliation: Hematology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Department of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain.
authors.forename: Alberto Chaparro
authors.initials: AC
authors.lastname: Gil
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Vidal-Castiñeira
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Márquez-Kisinousky
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Paula Díaz
authors.initials: PD
authors.lastname: Bulnes
authors.affiliation: Hematology Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Amelia Martinez
authors.initials: AM
authors.lastname: Marin
authors.affiliation: Hematology Service, Hospital General Universitario Santa Lucía, Cartagena, Murcia, Spain.
authors.forename: Maria Carmen García
authors.initials: MCG
authors.lastname: Garay
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Suarez-Alvarez
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Larrea
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism; D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
chemical_list: D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019717:Tissue Inhibitor of Metalloproteinase-3; C423230:ULBP2 protein, human; D000077209:Decitabine; D000072198:ADAM17 Protein; D001374:Azacitidine
keywords: DNA methylation; NKG2D; NKG2DL; TIMP3; acute myeloid leukemia (AML)