title: A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo.
abstract: We previously demonstrated that PU.1 expression is down-regulated in the majority of myeloma cell lines and primary myeloma cells from patients. We introduced the tet-off system into the human myeloma cell lines U266 and KMS12PE that conditionally express PU.1 and demonstrated that PU.1 induces cell cycle arrest and apoptosis in myeloma cells in vitro. Here, we established a mouse xenograft model of myeloma using these cell lines to analyze the effects of PU.1 on the phenotype of myeloma cells in vivo. When doxycycline was added to the drinking water of mice engrafted with these myeloma cells, all mice had continuous growth of subcutaneous tumors and could not survived more than 65 days. In contrast, mice that were not exposed to doxycycline did not develop subcutaneous tumors and survived for at least 100 days. We next generated mice engrafted with subcutaneous tumors 5-10 mm in diameter that were induced by exposure to doxycycline. Half of the mice stopped taking doxycycline-containing water, whereas the other half kept taking the water. Although the tumors in the mice taking doxycycline continued to grow, tumor growth in the mice not taking doxycycline was significantly suppressed. The myeloma cells in the tumors of the mice not taking doxycycline expressed PU.1 and TRAIL and many of such cells were apoptotic. Moreover, the expression of a cell proliferation marker Ki67 was significantly decreased in tumors from the mice not taking doxycycline, compared with that of tumors from the mice continuously taking doxycycline. The present data strongly suggest that PU.1 functions as a tumor suppressor of myeloma cells in vivo.
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Endo
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Shikiko
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Nina
authors.initials: N
authors.lastname: Ueno
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Hiro
authors.initials: H
authors.lastname: Tatetsu
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hata
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: yokuno@gpo.kumamoto-u.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okuno
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015996:Survival Rate; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C505654:Tnfsf10 protein, mouse
keywords: Apoptosis; Cell cycle arrest; Multiple myeloma; PU.1; Tumor suppressor; Xenograft model