title: Upregulation of NKG2D ligands in acute lymphoblastic leukemia and non-Hodgkin lymphoma cells by romidepsin and enhanced in vitro and in vivo natural killer cell cytotoxicity.
abstract: OBJECTIVE
  There is a critical need to prevent and/or treat hematological relapse after allogeneic hematopoietic stem cell transplantation. The activating NKG2D receptor expressed on natural killer (NK) cells, when engaged by its corresponding ligands (MIC A/B), activates NK cells to become cytotoxic against malignant cells.
  
  
  METHODS
  We incubated acute lymphoblastic leukemia and non-Hodgkin lymphoma cells for 24 h with 10 ng/mL of romidepsin. Flow cytometry was performed to demonstrate changes in surface expression of NKG2D ligands MIC A/B. In vitro and in vivo cytotoxicity was measured by means of modified Europium assay, and non-obese diabetic/severe combined immunodeficiency mice were xenografted with RS 4:11 cells.
  
  
  RESULTS
  We demonstrated an approximately 50, 200, 1300 and 180-fold increase in the number of cells positive for the surface expression of MIC A/B in RS 4:11 (P < 0.001), REH (P < 0.001), Ramos (P < 0.001) and Jurkat cells (P < 0.001), respectively. We further demonstrated a significant increase in NK cell-mediated in vitro cytotoxicity against RS 4:11 (P < 0.004), Ramos (P < 0.05), Jurkat (P < 0.001) and REH cells (P < 0.01), respectively. Romidepsin-mediated NK cytotoxicity was blocked by pre-incubating NK cells with anti-NKG2D-Fc in RS 4:11 (P < 0.03) and Ramos cells (P < 0.01), respectively. Finally, non-obese diabetic/severe combined immunodeficiency mice xenografted with RS 4:11 cells had a significant increase in survival (P < 0.02) in mice treated with romidepsin and interleukin-2-activated NK cells compared with each of these other treatment groups.
  
  
  CONCLUSIONS
  Romidepsin significantly enhanced in vitro and in vivo NK cell cytotoxicity mediated in part by increased MIC A/B expression on malignant cells. This translational approach of the use of romidepsin and interleukin-2-activated NK cells should be considered in patients with relapsed/refractory leukemia or lymphoma.
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, USA. Electronic address: ps2087@columbia.edu.
authors.forename: Prakash
authors.initials: P
authors.lastname: Satwani
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, USA.
authors.forename: Sejal
authors.initials: S
authors.lastname: Bavishi
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, USA.
authors.forename: Aniket
authors.initials: A
authors.lastname: Saha
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, New York, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Ayello
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, New York, USA.
authors.forename: Carmella
authors.initials: C
authors.lastname: van de Ven
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, New York, USA.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, New York, USA; Department of Medicine, New York Medical College, Valhalla, New York, USA; Department of Pathology, New York Medical College, Valhalla, New York, USA; Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, USA; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D047630:Depsipeptides / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008024:Ligands; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D047630:Depsipeptides; D015395:Histocompatibility Antigens Class I; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; C087123:romidepsin
keywords: NKG2D; leukemia; lymphoma; natural killer cells; romidepsin