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Systemic microRNA-34a delivery induces apoptosis and abrogates growth of diffuse large B-cell lymphoma in vivo

Leukemia volume 26, pages 2421–2424 (2012)Cite this article

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Diffuse large B-cell lymphoma (DLBCL) accounts for ∼30% of all B-cell lymphomas. The standard therapy consists of three chemotherapeutics (cyclophosphamide, doxorubicin and vincristine) combined with the steroid prednisone (CHOP) and/or the CD20-specific antibody rituximab.1 Two major subtypes of DLBCL are distinguished based on gene expression profiles that resemble those of activated B cells and germinal center B cells (ABC and GC types).2 We have reported recently that the expression of post-transcriptionally active small regulatory RNAs (microRNAs (miRNAs)) with tumor-suppressive properties3, 4, 5 is strongly deregulated in both nodal and extranodal DLBCL relative to indolent lymphomas arising at the same sites.6 All examined DLBCL cases exhibited a consistent signature of downregulated miRNAs independent of their location, which shared the common feature of being repressed by the transcription factor Myc. Myc was indeed found to be overexpressed in most analyzed cases of extranodal DLBCL, but not the corresponding indolent lymphomas. One miRNA in particular, miR-34a, emerged as a potent tumor-suppressor miRNA with the potential to inhibit the proliferation of various DLBCL cell lines.6 The tumor-suppressive activity of miR-34a could be attributed to the specific knockdown of FoxP1, a transcription factor and known target of miR-34a,6, 7 whose overexpression is associated with inferior prognosis in DLBCL patients.8

To investigate the mechanism underlying the tumor-suppressive effects of miR-34a replacement in vivo, we compared proliferation and apoptosis parameters in the two treatment groups. Explanted cells from miR-34a-treated tumors proliferated only marginally less than control cells as determined by [3H] thymidine incorporation (Supplementary Figure 4). In contrast, immunohistochemical staining for activated caspase-3 revealed significant differences in the fraction of early as well as late apoptotic cells in the tumor mass (Figures 1e and f). Taken together, the results provide evidence that DLBCL may be sensitive to a therapeutic strategy aimed at reintroducing miR-34a due to the strong proapoptotic properties of the miRNA.

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Acknowledgements

We would like to thank Stephan Dirnhofer and Sergio Cogliatti for helpful discussions. This study was funded by grants from the Swiss Cancer League and the Zurich University Research Priority Program in Systems Biology to AM.

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Authors and Affiliations

  1. Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland

    V J Craig, M Flori, C A Schmid & A Müller

  2. Institute of Pathology, University of Basel, Basel, Switzerland

    A Tzankov

  3. Mirna Therapeutics, Inc., Austin, TX, USA

    A G Bader

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  1. V J Craig
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  2. A Tzankov
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  3. M Flori
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  4. C A Schmid
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Correspondence to A G Bader or A Müller.

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Competing interests

AGB is an employee of Mirna Therapeutics, Inc., which develops miRNA-based therapeutics. All the other authors declare no conflict of interest.

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Craig, V., Tzankov, A., Flori, M. et al. Systemic microRNA-34a delivery induces apoptosis and abrogates growth of diffuse large B-cell lymphoma in vivo. Leukemia 26, 2421–2424 (2012). https://doi.org/10.1038/leu.2012.110

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