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Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL–Expressing Hematopoietic Progenitors in a Mouse Model

¹ Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University; ² Department of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto, Japan; and ³ Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan

Requests for reprints: Nagahiro Minato, Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4659; Fax: 81-75-753-4403; E-mail: minato{at}imm.med.kyoto-u.ac.jp.

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. (Cancer Res 2006; 66(20): 9967-76)

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