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High incidence of acute promyelocytic leukemia specifically induced by N-nitroso-N-methylurea (NMU) in Sprague–Dawley rats

  • Genotoxicity and Carcinogenicity
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Abstract

Carcinogenic agents such as N-methyl-N-nitrosourea can cause tumors. The aims of the present study were to evaluate and classify a subtype of AML (acute myeloid leukemia) that was induced by NMU. According to previous publications, NMU induces not only mammary cancer but also leukemia in Sprague–Dawley (S-D) rats. However, the subtype of leukemia involved in NMU-treated rats is unknown. We found that both organ weight and relative organ weights were significantly higher in NMU-exposed rats than in controls. Morphological changes of rat livers and spleens were assessed by histological evaluation (H&E staining), which found that these tissues were abnormal in appearance. Also, cytological examination of the blood showed immature white blood cells in a smear using Liu’s and Papanicolaou stains, indicating that gross abnormalities and histopathological changes were pathologically observed. NMU leukemia incidence was 97.1%. In this study, immunohistochemical (IHC) analysis was valuable in classifying the leukemia of poorly differentiated blasts induced by NMU. Paraffin blocks were stained for MPO, CD3, CD15, CD20, and CD34 markers. The NMU-induced group was positive for MPO, but negative for CD3, CD15, CD20, and CD34. These CD markers suggest that they are useful in helping diagnose APL (M3) leukemia. The model of NMU-induced leukemogenesis in an S-D rat suggests a more definite way to classify APL. This APL will provide an important tool for chemical carcinogenesis and leukemia studies.

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Abbreviations

NMU:

N-methyl-N-nitrosourea

AML:

Acute myeloid leukemia

S-D rats:

Sprague–Dawley rats

H&E stain:

Hematoxylin and eosin stain

IHC stain:

Immunohistochemical stain

MPO stain:

Myeloperoxidase stain

PAS stain:

Periodic acid-Schiff stain

CBC:

Complete blood count

WBC:

White blood cell

RBC:

Red blood cell

PLT:

Platelet

Hb:

Hemoglobin

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

CD marker:

Cluster of differentiation marker

O 6-meG:

O 6-methylguanine

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Acknowledgments

This work was supported by the grants from the Department of Health (DOH 098-TD-F-1B-098008), and the National Science Council (NSC 98-2313-B-040-005-MY2), Taiwan.

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Institute of Biochemistry and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung, 402, Taiwan

    Yun-Ching Chang & Chau-Jong Wang

  2. Department of Medical Research, Chung-Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Road, Taichung, 402, Taiwan

    Yun-Ching Chang & Chau-Jong Wang

  3. Department of Pathology, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Road, Taichung, 402, Taiwan

    Jeng-Dong Hsu, Wea-Lung Lin & Yi-Ju Lee

  4. Department of Pathology, School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung, 402, Taiwan

    Jeng-Dong Hsu, Wea-Lung Lin & Yi-Ju Lee

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  1. Yun-Ching Chang
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Correspondence to Chau-Jong Wang.

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Yun-Ching Chang and Jeng-Dong Hsu contributed equally to the present study and therefore share co-first author.

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Chang, YC., Hsu, JD., Lin, WL. et al. High incidence of acute promyelocytic leukemia specifically induced by N-nitroso-N-methylurea (NMU) in Sprague–Dawley rats. Arch Toxicol 86, 315–327 (2012). https://doi.org/10.1007/s00204-011-0753-7

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