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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 expressedmore » 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. - Highlights: • PU.1 suppresses xenograft myeloma cell growth and prolongs survival periods of mice. • PU.1 induces TRAIL expression and apoptosis in myeloma cells in vivo. • PU.1 suppresses Ki67 expression in myeloma cells in vivo. • Up-regulation of PU.1 is a promising strategy for generating anti-myeloma agents.« less

Authors:
; ; ; ; ; ;  [1]; ;  [2];  [1];  [1]
  1. Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 (Japan)
  2. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan)
Publication Date:
OSTI Identifier:
22697008
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 486; Journal Issue: 4; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL CYCLE; CELL PROLIFERATION; DRINKING WATER; IN VIVO; MICE; NEOPLASMS; PLANT GROWTH

Citation Formats

Nishimura, Nao, Endo, Shinya, Ueno, Shikiko, Ueno, Nina, Tatetsu, Hiro, Hirata, Shinya, Hata, Hiroyuki, Komohara, Yoshihiro, Takeya, Motohiro, Mitsuya, Hiroaki, and Okuno, Yutaka. A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2017.03.124.
Nishimura, Nao, Endo, Shinya, Ueno, Shikiko, Ueno, Nina, Tatetsu, Hiro, Hirata, Shinya, Hata, Hiroyuki, Komohara, Yoshihiro, Takeya, Motohiro, Mitsuya, Hiroaki, & Okuno, Yutaka. A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo. United States. doi:10.1016/J.BBRC.2017.03.124.
Nishimura, Nao, Endo, Shinya, Ueno, Shikiko, Ueno, Nina, Tatetsu, Hiro, Hirata, Shinya, Hata, Hiroyuki, Komohara, Yoshihiro, Takeya, Motohiro, Mitsuya, Hiroaki, and Okuno, Yutaka. Sat . "A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo". United States. doi:10.1016/J.BBRC.2017.03.124.
@article{osti_22697008,
title = {A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo},
author = {Nishimura, Nao and Endo, Shinya and Ueno, Shikiko and Ueno, Nina and Tatetsu, Hiro and Hirata, Shinya and Hata, Hiroyuki and Komohara, Yoshihiro and Takeya, Motohiro and Mitsuya, Hiroaki and Okuno, Yutaka},
abstractNote = {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. - Highlights: • PU.1 suppresses xenograft myeloma cell growth and prolongs survival periods of mice. • PU.1 induces TRAIL expression and apoptosis in myeloma cells in vivo. • PU.1 suppresses Ki67 expression in myeloma cells in vivo. • Up-regulation of PU.1 is a promising strategy for generating anti-myeloma agents.},
doi = {10.1016/J.BBRC.2017.03.124},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 486,
place = {United States},
year = {Sat May 13 00:00:00 EDT 2017},
month = {Sat May 13 00:00:00 EDT 2017}
}