title: Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+leukemia patients treated with dasatinib.
abstract: Dasatinib treatment markedly increases the number of large granular lymphocytes (LGLs) in a proportion of Ph+leukemia patients, which associates with a better prognosis. The lymphocytosis is predominantly observed in cytomegalovirus (CMV)-seropositive patients, yet detectable CMV reactivation exists only in a small fraction of patients. Thus, etiology of the lymphocytosis still remains unclear. Here, we identified NK cells as the dominant LGLs expanding in dasatinib-treated patients, and applied principal component analysis (PCA) to an extensive panel of NK cell markers to explore underlying factors in NK cell activation. PCA displayed phenotypic divergence of NK cells that reflects CMV-associated differentiation and genetic differences, and the divergence was markedly augmented in CMV-seropositive dasatinib-treated patients. Notably, the CMV-associated highly differentiated status of NK cells was already observed at leukemia diagnosis, and was further enhanced after starting dasatinib in virtually all CMV-seropositive patients. Thus, the extensive characterization of NK cells by PCA strongly suggests that CMV is an essential factor in the NK cell activation, which progresses stepwise during leukemia and subsequent dasatinib treatment most likely by subclinical CMV reactivation. This study provides a rationale for the exploitation of CMV-associated NK cell activation for treatment of leukemias.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ishiyama
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kitawaki
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Department of Management Science, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sozu
authors.affiliation: Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Takatsuki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Anzai
authors.affiliation: Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Takatsuki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Hematology, Wakayama Red Cross Hospital, Wakayama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nohgawa
authors.affiliation: Department of Hematology, Wakayama Red Cross Hospital, Wakayama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hatanaka
authors.affiliation: Department of Hematology, Kitano Hospital, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Arima
authors.affiliation: Department of Hematology, Kobe City Medical Center, Kobe, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Hematology, Kobe City Medical Center, Kobe, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tabata
authors.affiliation: Department of Hematology, Kokura Memorial Hospital, Kitakyusyu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Onaka
authors.affiliation: Department of Hematology and Oncology, Shiga Medical Center for Adults, Moriyama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Oka
authors.affiliation: The Center for Hematological Diseases, Takeda General Hospital, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakabo
authors.affiliation: Department of Hematology, The Japan Baptist Hospital, Kyoto, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Amakawa
authors.affiliation: Department of Hematology, Kyoto City Hospital, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Department of Hematology, Kyoto-Katsura Hospital, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Moriguchi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: A
authors.identifier: 0000-0001-7678-4284
authors.initials: A
authors.lastname: Takaori-Kondo
authors.affiliation: Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kadowaki
mesh_terms: D003587:Cytomegalovirus; D000069439:Dasatinib / Q000627:therapeutic use*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000382:microbiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000276:immunology*; D025341:Principal Component Analysis; D014775:Virus Activation
chemical_list: D000069439:Dasatinib