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Acute myeloid leukemia

Benzene induces rapid leukemic transformation after prolonged hematotoxicity in a murine model

Leukemia volume 35, pages 595–600 (2021)Cite this article

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Benzene is an important industrial chemical and ubiquitous environmental mutagen known to induce hematological malignancies particularly leukemia [1]. The development of benzene-induced leukemia takes an average of 11.4 years to occurs in workers chronically exposed to high levels of benzene [2]. Before the onset of the malignancy, benzene workers experience a strong and prolonged hematotoxicity characterized by significantly reduced white blood cell counts, and in severe forms, pancytopenia or anemia, and the later has been referred to as benzene poisoning (BP) [3]. These observations are consistent with in vitro findings that benzene inhibit hematopoietic growth and self-renewal through induction of DNA double strand breaks and adducts of bone marrow DNA [4]. Benzene-induced hematotoxicity is associated with future risk of developing haematological malignancy. While benzene exposure has an overall 7-fold risk for development of leukemia, BP is associated with a 71-fold risk for development of the acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) in human [2, 5]. Malignant transformation in these benzene-exposed workers can take place in a very short time, as evident by rapid 10-fold expansion of white blood cell (WBC) within 6-month in reported long-term exposure BP cases [3].

While these population-based cohort studies characterize key aspects of this unique entity of AML in humans, models are needed to recapitulate this distinct evolutionary trajectory of benzene-induced leukemia. Such model will be a powerful tool to explore the pathobiology and the underlying molecular mechanisms of benzene-induced carcinogenesis. The inhibitory effects of benzene on hematopoietic cells have been extensively characterized in vitro and in vivo [1]. However, hematotoxicity does not lead to leukemic transformation in these systems. In the efforts to develop cancer models, benzene treatment induced mostly lymphoma [6], a different type of blood cancer from what have been commonly observed in benzene-exposed human population. Benzene also has been shown to promote tumor development in transgenic mice carrying Trp53 or Ras mutation [6, 7]. The toxic effect on hematopoiesis, however, was not observed in these mice. Therefore, the continum of hematotoxicity and malignant transformation in the development of benzene-induced human leukemia has been difficult to model.

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Fig. 1: Benzene induces rapid leukemic transformation after prolonged hematotoxicity in transplant Mll–Af9 murine model.
Fig. 2: Transcriptome and genome analysis of AML cells among benzene group and air control group.

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Acknowledgements

This work was supported by the Beijing Natural Science Foundation (No. 7182118), the National Natural Science Foundation of China (No. 81641009), the Social Development Project of Jiangsu Province (No. BE2017659), and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (to C.A.L.). We acknowledge Bing Liu at Academy of Military Medical Sciences for kindly providing the male B6.SJL mouse strain. We are grateful to Nan Lian at West China School of Public Health for technical assistance.

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  1. These authors contributed equally: Jianxin Zhao, Pinpin Sui, Bo Wu

Authors and Affiliations

  1. Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China

    Jianxin Zhao, Bo Wu, Yedan Lu, Fenxia Hou, Xiurong Cheng, Shiwei Cui, Jiayang Song & Caihong Xing

  2. CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Pinpin Sui, Aili Chen & Qian-fei Wang

  3. China National Center for Bioinformation, Beijing, China

    Pinpin Sui, Aili Chen & Qian-fei Wang

  4. University of Chinese Academy of Sciences, Beijing, China

    Pinpin Sui & Qian-fei Wang

  5. Chinese Academy of Inspection and Quarantine, Beijing, China

    Bo Wu

  6. Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA

    Gang Huang

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Contributions

JZ and BW performed experiments; CX, QW, HG, and AC designed experiments; JZ, PS, and JS analyzed data; YL, FH, and XC established techniques of flow cytometry; SC helped to monitor the concentration of benzene; QWang, CX, JZ, and PS wrote the manuscript. All authors approved and take shared responsibility for the final submitted version of the manuscript.

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Correspondence to Caihong Xing or Qian-fei Wang.

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Zhao, J., Sui, P., Wu, B. et al. Benzene induces rapid leukemic transformation after prolonged hematotoxicity in a murine model. Leukemia 35, 595–600 (2021). https://doi.org/10.1038/s41375-020-0894-x

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