title: S100A9 induces differentiation of acute myeloid leukemia cells through TLR4.
abstract: S100A8 and S100A9 are calcium-binding proteins predominantly expressed by neutrophils and monocytes and play key roles in both normal and pathological inflammation. Recently, both proteins were found to promote tumor progression through the establishment of premetastatic niches and inhibit antitumor immune responses. Although S100A8 and S100A9 have been studied in solid cancers, their functions in hematological malignancies remain poorly understood. However, S100A8 and S100A9 are highly expressed in acute myeloid leukemia (AML), and S100A8 expression has been linked to poor prognosis in AML. We identified a small subpopulation of cells expressing S100A8 and S100A9 in AML mouse models and primary human AML samples. In vitro and in vivo analyses revealed that S100A9 induces AML cell differentiation, whereas S100A8 prevents differentiation induced by S100A9 activity and maintains AML immature phenotype. Treatment with recombinant S100A9 proteins increased AML cell maturation, induced growth arrest, and prolonged survival in an AML mouse model. Interestingly, anti-S100A8 antibody treatment had effects similar to those of S100A9 therapy in vivo, suggesting that high ratios of S100A9 over S100A8 are required to induce differentiation. Our in vitro studies on the mechanisms/pathways involved in leukemic cell differentiation revealed that binding of S100A9 to Toll-like receptor 4 (TLR4) promotes activation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, and Jun N-terminal kinase signaling pathways, leading to myelomonocytic and monocytic AML cell differentiation. These findings indicate that S100A8 and S100A9 are regulators of myeloid differentiation in leukemia and have therapeutic potential in myelomonocytic and monocytic AMLs.
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Médecine, and.
authors.forename: Malika
authors.initials: M
authors.lastname: Laouedj
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Quebec City, QC, Canada; and.
authors.forename: Mélanie R
authors.initials: MR
authors.lastname: Tardif
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Médecine, and.
authors.forename: Laurine
authors.initials: L
authors.lastname: Gil
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Quebec City, QC, Canada; and.
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Raquil
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Quebec City, QC, Canada; and.
authors.forename: Asmaa
authors.initials: A
authors.lastname: Lachhab
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Quebec City, QC, Canada; and.
authors.forename: Martin
authors.identifier: 0000-0001-5033-4947
authors.initials: M
authors.lastname: Pelletier
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Quebec City, QC, Canada; and.
authors.forename: Philippe A
authors.identifier: 0000-0001-7177-7763
authors.initials: PA
authors.lastname: Tessier
authors.affiliation: Infectious and Immune Diseases Research Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec City, QC, Canada.|Département de Médecine, and.|CHU de Québec Hôpital Enfant-Jésus, Quebec City, QC, Canada.
authors.forename: Frédéric
authors.identifier: 0000-0003-0024-3611
authors.initials: F
authors.lastname: Barabé
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D009363:Neoplasm Proteins; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3