title: Dasatinib induces autophagy in mice with Bcr-Abl-positive leukemia.
abstract: Dasatinib, a second-generation tyrosine kinase inhibitor, is a highly effective treatment for Bcr-Abl-positive leukemia. However, the mechanism by which dasatinib induces cell death is unclear, particularly in vivo. Autophagy is a lysosomal degradation mechanism essential for cell survival and differentiation. Autophagy also protects cells from the effects of drugs, including those used to treat leukemia. Here, we report that dasatinib induces autophagy in Bcr-Abl-positive leukemia cell lines and further show the induction of autophagy in an immunodeficient mouse model of human Bcr-Abl-positive leukemia with central nervous system (CNS) infiltration. Autophagy was induced in bone marrow (BM) as well as cerebrospinal fluid (CSF). This study is the first to show that autophagy induction is one of the mechanisms underlying cell death in leukemic cells that infiltrate the CNS. Thus, autophagy may represent a novel therapeutic target for the treatment of Bcr-Abl leukemia with CNS infiltration.
authors.affiliation: School of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Morita
authors.affiliation: School of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.|Center for iPS Cell Research and Application, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nishinaka
authors.affiliation: Department of Pediatrics, Kyoto University Hospital, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Kyoto University Hospital, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saida
authors.affiliation: Department of Pediatrics, Kyoto University Hospital, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Hiramatsu
authors.affiliation: School of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kamikubo
authors.affiliation: Department of Pediatrics, Kyoto University Hospital, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.affiliation: School of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan. adachiso@kuhp.kyoto-u.ac.jp.
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000473:pathology; D002555:Cerebrospinal Fluid; D000069439:Dasatinib / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D017254:Leukemic Infiltration / Q000188:drug therapy; D051379:Mice
chemical_list: D000069439:Dasatinib
keywords: Autophagy; Bcr-Abl; Caspase-independent cell death; Dasatinib; Leukemia