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miR-155 drives oncogenesis by promoting and cooperating with mutations in the c-Kit oncogene

Oncogene volume 38, pages 2151–2161 (2019)Cite this article

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Abstract

MicroRNAs (miRNAs) have emerged as crucial players in the development and maintenance of disease. miR-155 is an inflammation-associated, oncogenic miRNA, frequently overexpressed in hematological malignancies and solid tumors. However, the mechanism of oncogenesis by miR-155 is not well characterized, and research has focused primarily on individual, direct targets, which does not recapitulate the complexities of cancer. Using a powerful, inducible transgenic mouse model that overexpresses miR-155 and develops miR-155-addicted hematological malignancy, we describe here a multi-step process of oncogenesis by miR-155, which involves cooperation between miR-155, its direct targets, and other oncogenes. miR-155 is known to target DNA-repair proteins, leading to a mutator phenotype, and we find that over 93% of tumors in our miR-155 overexpressing mice contain activating mutations in a single oncogene, c-Kit. Treating mice with dasatinib or imatinib, which target c-Kit, resulted in complete tumor regression, indicating that c-Kit activity is crucial in the oncogenic process. Interestingly, c-Kit expression is high when miR-155 is overexpressed, indicating further cooperation between miR-155 and c-Kit. Our findings support a multi-step model of oncogenesis by miR-155 in which miR-155 promotes both a mutator phenotype and a cellular environment particularly susceptible to mutations in a given oncogene.

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Acknowledgements

We wish to thank Bohyung Yoon and Eleni Anastasiadou for assistance with animal care and Jacob Witten for critical reading of the manuscript. The work was supported by the Ludwig Center at Harvard.

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Author notes

  1. Christopher J. Cheng

    Present address: Casebia Therapeutics, 610 Main Street, Cambridge, MA, 02139, USA

Authors and Affiliations

  1. HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02115, USA

    Lisa W. Witten & Frank J. Slack

  2. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, 06511, USA

    Christopher J. Cheng

Authors
  1. Lisa W. Witten
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Correspondence to Frank J. Slack.

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Witten, L.W., Cheng, C.J. & Slack, F.J. miR-155 drives oncogenesis by promoting and cooperating with mutations in the c-Kit oncogene. Oncogene 38, 2151–2161 (2019). https://doi.org/10.1038/s41388-018-0571-y

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