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Oncogenes, Fusion Genes and Tumor Suppressor Genes

BCR-ABL1–positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia

Leukemia volume 28, pages 1666–1675 (2014)Cite this article

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Abstract

Malignant transformation of normal hematopoietic transplants induced by residual leukemia cells is considered as a pivotal mechanism of donor cell leukemia (DCL). The effects of leukemia cell–derived microvesicles (MVs) in this transformation were examined. We found that MVs derived from K562 leukemia cells contained the breakpoint cluster region–Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA. Following incubation with BCR-ABL1–positive MVs, mononuclear cells derived from normal transplants exhibited a leukemia-like malignant phenotype both in vitro and in vivo. Horizontal transfer of BCR-ABL1 mRNA from MVs into the recipient cells was critical to the transformation. Relative genomic instability was observed and considered the main mechanism in the recipient cells. MVs contributed to genomic instability by two distinct pathways: via consequent overexpression of activation-induced cytidine deaminase and reactive oxygen species, which mediated DNA breakage and recombination; and via upregulation of methyltransferases and global DNA hypermethylation. We demonstrated that BCR-ABL1–positive MVs could initiate malignant transformation of normal hematopoietic transplants through genomic instability, which might serve as a convenient and operable model for investigating leukemogenesis, especially for DCL. Furthermore, MVs themselves could act as an early warning indicator and a novel tool to detect and prevent the occurrence of DCL.

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Acknowledgements

We thank Professor Zhijian Xiao (Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China) for his kind supply of Imatinib. This work was supported by grants from the National Natural Science Foundation of China (Nos. 81170497 and 81170498).

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  1. X Zhu and Y You: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    X Zhu, Y You, Q Li, C Zeng, F Fu, P Zou, Z Zhong, Y Wu, Q Li, F Kong & Z Chen

  2. Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    A Guo & H Zhang

  3. Department of Hematology, the Central Hospital, Wuhan, People’s Republic of China

    H Wang

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Zhu, X., You, Y., Li, Q. et al. BCR-ABL1–positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia. Leukemia 28, 1666–1675 (2014). https://doi.org/10.1038/leu.2014.51

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