The role of TLR8 signaling in acute myeloid leukemia differentiation

• Published in: Leukemia 2015-04, Vol.29 (4), p.918-926
• Main Authors: Ignatz-Hoover, J J, Wang, H, Moreton, S A, Chakrabarti, A, Agarwal, M K, Sun, K, Gupta, K, Wald, D N
• Format: Article
• Language: English
• Subjects: 13; 13/95; 631/67/1990/283/1897; 64; 692/308/2778; 96; 96/106; 96/31; 96/95; Activation; Acute myeloid leukemia; Agonists; Animals; Antineoplastic Agents - pharmacology; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cancer Research; Cell Differentiation; Cellular signal transduction; Critical Care Medicine; Differentiation; Female; Gene expression; Gene Expression Regulation, Leukemic; Growth inhibition; Health aspects; Hematology; HL-60 Cells; Humans; Imidazoles - pharmacology; Immunodeficiency; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Medicine; Medicine & Public Health; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred NOD; Mice, SCID; MyD88 protein; Myeloid cells; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Myeloid leukemia; Oncology; original-article; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Retinoic acid; Signal Transduction - drug effects; Signal Transduction - genetics; Therapy; TLR7 protein; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-Like Receptor 8 - agonists; Toll-Like Receptor 8 - genetics; Toll-Like Receptor 8 - metabolism; Toll-like receptors; Tretinoin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.293

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.