Inducible nitric oxide synthase mediates DNA double strand breaks in Human T-Cell Leukemia Virus Type 1-induced leukemia/lymphoma.
BACKGROUND
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive and fatal malignancy of CD4(+) T-lymphocytes infected by the Human T-Cell Virus Type 1 (HTLV-1). The molecular mechanisms of transformation in ATLL have not been fully elucidated. However, genomic instability and cumulative DNA damage during the long period of latency is believed to be essential for HTLV-1 induced leukemogenesis. In addition, constitutive activation of the NF-κB pathway was found to be a critical determinant for transformation. Whether a connection exists between NF-κB activation and accumulation of DNA damage is not clear. We recently found that the HTLV-1 viral oncoprotein, Tax, the activator of the NF-κB pathway, induces DNA double strand breaks (DSBs).


RESULTS
Here, we investigated whether any of the NF-κB target genes are critical in inducing DSBs. Of note, we found that inducible nitric oxide synthase (iNOS) that catalyzes the production of nitric oxide (NO) in macrophages, neutrophils and T-cells is over expressed in HTLV-1 infected and Tax-expressing cells. Interestingly, we show that in HTLV-1 infected cells, iNOS expression is Tax-dependent and specifically requires the activation of the classical NF-κB and JAK/STAT pathways. A dramatic reduction of DSBs was observed when NO production was inhibited, indicating that Tax induces DSBs through the activation of NO synthesis.


CONCLUSIONS
Determination of the impact of NO on HTLV-1-induced leukemogenesis opens a new area for treatment or prevention of ATLL and perhaps other cancers in which NO is produced.
Division of Molecular Oncology, Department of Medicine Campus, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA. hbaydoun@dom.wustl.edu.
Hicham H
HH
Baydoun
Division of Molecular Oncology, Department of Medicine Campus, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA. mcherian@dom.wustl.edu.
Mathew A
MA
Cherian
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA. green.466@osu.edu.
Patrick
P
Green
Division of Molecular Oncology, Department of Medicine Campus, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA. lratner@dom.wustl.edu.|Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. lratner@dom.wustl.edu.
Lee
L
Ratner
D000328:Adult; D000578:Amidines / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000378:metabolism*; D016355:Genes, pX; D015490:HTLV-I Infections / Q000235:genetics / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D000578:Amidines; D003374:Coumarins; D016356:Gene Products, tax; C470914:N-(6-bromo-7-hydroxycoumarin-4-yl)methoxycarbonyl-N-(3-(aminomethyl)benzyl)acetamide; D016328:NF-kappa B; D050791:STAT Transcription Factors; C514970:tax protein, Human T-lymphotrophic virus 1; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D053612:Janus Kinases