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Transcriptional Control and Signal Transduction

The role of TLR8 signaling in acute myeloid leukemia differentiation

Leukemia volume 29, pages 918–926 (2015)Cite this article

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Abstract

Acute myeloid leukemia (AML) is an aggressive disease with a poor 5-year survival of 21% that is characterized by the differentiation arrest of immature myeloid cells. For a rare subtype of AML (acute promyeloctyic leukemia, 5–10% of cases), all-trans retinoic acid therapy removes the differentiation block, yielding over a 90% cure rate. However, this treatment is not effective for the other 90–95% of AML patients, suggesting that new differentiation strategies are needed. Interestingly, differentiation is induced in normal hematopoietic cells through Toll-like receptor (TLR) stimulation and TLRs are expressed on AML cells. We present evidence that the TLR8 activation promotes AML differentiation and growth inhibition in a TLR8/MyD88/p38-dependent manner. We also show that that TLR7/TLR8 agonist, R848, considerably impairs the growth of human AML cells in immunodeficient mice. Our data suggests TLR8 activation has direct anti-leukemic effects independent of its immunomodulating properties that are currently under investigation for cancer therapy. Taken together, our results suggest that treatment with TLR8 agonists may be a promising new therapeutic strategy for AML.

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Acknowledgements

This research was supported by the Athymic Animal and Xenograft Core Facility and the Cytometery and Imaging Microscopy Core Facility of the Case Comprehensive Cancer Center (P30CA043703) as well as the following grants: NIH T32 CA59366-17 /GM007250 (JJI-H) and National Natural Science Foundation of China 30400520 (HW).

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Author notes

  1. J J Ignatz-Hoover and H Wang: JJI-H and HW contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    J J Ignatz-Hoover, H Wang, S A Moreton, K Sun, K Gupta & D N Wald

  2. Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

    H Wang

  3. Invenio Therapeutics, Cleveland, OH, USA

    A Chakrabarti & M K Agarwal

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  1. J J Ignatz-Hoover
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Correspondence to D N Wald.

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Ignatz-Hoover, J., Wang, H., Moreton, S. et al. The role of TLR8 signaling in acute myeloid leukemia differentiation. Leukemia 29, 918–926 (2015). https://doi.org/10.1038/leu.2014.293

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