title: The role of TLR8 signaling in acute myeloid leukemia differentiation.
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.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland OH.
authors.forename: James J
authors.initials: JJ
authors.lastname: Ignatz-Hoover
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland OH.|Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland OH.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Moreton
authors.affiliation: Invenio Therapeutics, Cleveland, OH.
authors.forename: Amit
authors.initials: A
authors.lastname: Chakrabarti
authors.affiliation: Invenio Therapeutics, Cleveland, OH.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Agarwal
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland OH.
authors.forename: Kevin
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland OH.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland OH.
authors.forename: David N
authors.initials: DN
authors.lastname: Wald
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D048051:p38 Mitogen-Activated Protein Kinases; C402365:resiquimod