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Disruption of NAD(P)H:Quinone Oxidoreductase 1 Gene in Mice Leads to Radiation-Induced Myeloproliferative Disease

¹ Department of Pharmacology, Baylor College of Medicine, ² Department of Pathology, Methodist Hospital, Houston, Texas; and ³ Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland

Requests for reprints: Anil K. Jaiswal, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201. Phone: 410-706-2285; Fax: 410-706-0032; E-mail: ajaiswal{at}som.umaryland.edu.

Key Words: NAD(P)H:quinone oxidoreductase1 (NQO1) • NQO1 knockout mice • -radiation • apoptosis and differentiation • myeloproliferative diseases

NAD(P)H:quinone oxidoreductase 1 null (NQO1^–/–) mice exposed to 3 Gy of -radiation showed an increase in neutrophils, bone marrow hypercellularity, and enlarged lymph nodes and spleen. The spleen showed disrupted follicular structure, loss of red pulp, and granulocyte and megakarocyte invasion. Blood and histologic analysis did not show any sign of infection in mice. These results suggested that exposure of NQO1^–/– mice to -radiation led to myeloproliferative disease. Radiation-induced myeloproliferative disease was observed in 74% of NQO1^–/– mice as compared with none in wild-type (WT) mice. NQO1^–/– mice exposed to -radiation also showed lymphoma tissues (32%) and lung adenocarcinoma (84%). In contrast, only 11% WT mice showed lymphoma and none showed lung adenocarcinoma. Exposure of NQO1^–/– mice to -radiation resulted in reduced apoptosis in granulocytes and lack of induction of p53, p21, and Bax. NQO1^–/– mice also showed increased expression of myeloid differentiation factors CCAAT/enhancer binding protein (C/EBP) and Pu.1. Intriguingly, exposure of NQO1^–/– mice to -radiation failed to induce C/EBP and Pu.1, as was observed in WT mice. These results suggest that decreased p53/apoptosis and increased Pu.1 and C/EBP led to myeloid hyperplasia in NQO1^–/– mice. The lack of induction of apoptosis and differentiation contributed to radiation-induced myeloproliferative disease in NQO1^–/– mice. [Cancer Res 2008;68(19):7915–22]

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				K. Iskander, R. J. Barrios, and A. K. Jaiswal NRH:Quinone Oxidoreductase 2-Deficient Mice Are Highly Susceptible to Radiation-Induced B-Cell Lymphomas Clin. Cancer Res., March 1, 2009; 15(5): 1534 - 1542. [Abstract] [Full Text] [PDF]