Oncotarget

Research Papers:

Evolution of malignant plasmacytoma cell lines from K14E7 Fancd2−/− mouse long-term bone marrow cultures

Xichen Zhang, Wen Hou, Michael W. Epperly, Lora Rigatti, Hong Wang, Darcy Franicola, Aranee Sivanathan, Joel S. Greenberger _

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Oncotarget. 2016; 7:68449-68472. https://doi.org/10.18632/oncotarget.12036

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Abstract

Xichen Zhang1, Wen Hou1, Michael W. Epperly1, Lora Rigatti2, Hong Wang1, Darcy Franicola1, Aranee Sivanathan1, Joel S. Greenberger1

1Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, 15232 PA, USA

2Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, 15260 PA, USA

Correspondence to:

Joel S. Greenberger, email: greenbergerjs@upmc.edu

Keywords: E7, HPV oncogene, human papillomavirus, Fanconi anemia, Fancd2−/− mice

Received: April 29, 2016     Accepted: September 02, 2016     Published: September 15, 2016

ABSTRACT

We tested the effect of expression of the Human Papilloma Virus (HPV E7) oncogene on hematopoiesis in long-term bone marrow cultures (LTBMCs) derived from K14E7 (FVB) Fancd2−/− (129/Sv), K14E7 Fancd2+/+, Fancd2−/−, and control (FVB X 129/Sv) Fl mice. K14E7 Fancd2−/− and Fancd2−/− LTBMCs showed decreased duration of production of total nonadherent hematopoietic cells and progenitors forming day 7 and day 14 multilineage CFU-GEMM colonies in secondary cultures (7 wks and 8 wks respectively) compared to cultures from K14E7 Fancd2+/+ (17 wks) or control mice (18 wks) p < 0.0001. Marrow stromal cell lines derived from both K14E7 Fancd2−/− and Fancd2−/− cultures were radiosensitive, as were IL-3 dependent hematopoietic progenitor cell lines derived from K14E7 Fancd2−/− cultures. In contrast, Fancd2−/− mouse hematopoietic progenitor cell lines and fresh marrow were radioresistant. K14E7 Fancd2−/− mouse freshly explanted bone marrow expressed no detectable K14 or E7; however, LTBMCs produced K14 positive factor-independent (FI) clonal malignant plasmacytoma forming cell lines in which E7 was detected in the nucleus with p53 and Rb. Transfection of an E6/E7 plasmid into Fancd2−/−, but not control Fancd2+/+ IL-3 dependent hematopoietic progenitor cell lines, increased cloning efficiency, cell growth, and induced malignant cell lines. Therefore, the altered radiobiology of hematopoietic progenitor cells and malignant transformation in vitro by K14E7 expression in cells of the Fancd2−/− genotype suggests a potential role of HPV in hematopoietic malignancies in FA patients.


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