title: Activation of Notch1 promotes development of human CD8(+) single positive T cells in humanized mice.
abstract: Notch1 mutations are found in more than 50% of human T cell acute lymphoblastic leukemia (T-ALL) cells. However, the functions of Notch1 for human T cell development and leukemogenesis are not well understood. To examine the role of Notch1, human hematopoietic stem cells (HSCs), which had been transduced with a constitutively active form of Notch1 (ICN1), were transplanted into severely immunodeficient NOD/Shi-scid-IL2rγ(null) (NOG) mice. We found that the great majority of the ICN1-expressing hematopoietic cells in the bone marrow expressed surface markers for T cells, such as CD3, CD4, and CD8, and that this T cell development was independent of the thymus. Accordingly, phenotypically mature CD8(+) single positive (SP) T cells were observed in the spleen. Furthermore, T-ALL developed in one NOG recipient mouse out of 26 that had been secondary transferred with the T cells developed in the first NOG mice. These results indicate that Notch1 signaling in HSCs promotes CD8(+) SP T cell development, and that T cell leukemogenesis may require additional oncogenic factors other than Notch1 activation.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Haji
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: So
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Isehara 259-1193, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.affiliation: Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mizuma
authors.affiliation: Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Electronic address: ishiin@med.tohoku.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000473:pathology
chemical_list: D051881:Receptor, Notch1
keywords: Humanized mouse; Notch1; T cell development