title: Role of SPA-1 in phenotypes of chronic myelogenous leukemia induced by BCR-ABL-expressing hematopoietic progenitors in a mouse model.
abstract: SPA-1 is a negative regulator of Rap1 signal in hematopoietic cells, and SPA-1-deficient mice develop myeloproliferative disorders (MPD) of long latency. In the present study, we showed that the MPDs in SPA-1(-/-) mice were associated with the increased hematopoietic stem cells expressing LFA-1 in bone marrow and their premature mobilization to spleen with extensive extramedullary hematopoiesis, resembling human chronic myelogenous leukemia (CML). We further showed that human BCR-ABL oncogene caused a partial down-regulation of endogenous SPA-1 gene expression in mouse hematopoietic progenitor cells (HPC) and immature hematopoietic cell lines. Although both BCR-ABL-transduced wild-type (wt) and SPA-1(-/-) HPC rapidly developed CML-like MPD when transferred to severe combined immunodeficient mice, the latter recipients showed significantly increased proportions of BCR-ABL(+) Lin(-) c-Kit(+) cells compared with the former ones. Serial transfer experiments revealed that spleen cells of secondary recipients of BCR-ABL(+) wt HPC failed to transfer MPD to tertiary recipients due to a progressive reduction of BCR-ABL(+) Lin(-) c-Kit(+) cells. In contrast, SPA-1(-/-) BCR-ABL(+) Lin(-) c-Kit(+) cells were sustained at high level in secondary recipients, and their spleen cells could transfer MPD to tertiary recipients, a part of which rapidly developed blast crisis. Present results suggest that endogenous SPA-1 plays a significant role in regulating expansion and/or survival of BCR-ABL(+) leukemic progenitors albeit partial repression by BCR-ABL and that Rap1 signal may represent a new molecular target for controlling leukemic progenitors in CML.
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kometani
authors.forename: Misayo
authors.initials: M
authors.lastname: Aoki
authors.forename: Shin
authors.initials: S
authors.lastname: Kawamata
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Shinozuka
authors.forename: Takumi
authors.initials: T
authors.lastname: Era
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hattori
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D009687:Nuclear Proteins; C091108:Sipa1 protein, mouse; D016044:Fusion Proteins, bcr-abl; D020827:rap1 GTP-Binding Proteins