title: p38 Mitogen-activated protein kinase inhibition enhances in vitro erythropoiesis of Fanconi anemia, complementation group A-deficient bone marrow cells.
abstract: Bone marrow failure in Fanconi anemia (FA) has been linked in part to overproduction of inflammatory cytokines, to which FA stem and progenitor cells are hypersensitive. In cell lines and murine models p38 mitogen-activated protein kinase (MAPK)-dependent tumor necrosis factor α (TNF-α) overexpression can be induced by the Toll-like receptors (TLRs) 4 and 7/8 ligands Lipopolysaccharide (LPS) and R848. Ex vivo exposure of FA stem cells to TNF-α suppresses their replication and selects preleukemic clones. Here we show that inhibition of p38 MAPK also reduces TLR4 and 7/8-mediated TNF-α production in primary human FA complementation group A (FANCA)-deficient monocytes from nine patients and demonstrate that, while p38 MAPK inhibition also enhances clonal growth of FANCA-deficient erythroid progenitors, the effect was mediated indirectly by the influence of the inhibitor on auxiliary cells, not erythroid colony-forming units themselves. Taken together, these results support the view that inhibition of the p38 MAPK pathway in monocytes may improve hematopoiesis in FANCA patients.
authors.affiliation: Hematology Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Johanna
authors.initials: J
authors.lastname: Svahn
authors.affiliation: Hematology Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Lanza
authors.affiliation: Oregon Health & Science University, Portland, OR, United States.
authors.forename: Keaney
authors.initials: K
authors.lastname: Rathbun
authors.affiliation: Oregon Health & Science University, Portland, OR, United States.
authors.forename: Grover
authors.initials: G
authors.lastname: Bagby
authors.affiliation: DIFAR-Biochemistry Laboratory, Department of Pharmacology, University of Genoa, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ravera
authors.affiliation: Laboratorio Diagnosi Pre e Postnatale Malattie Metaboliche, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsolini
authors.affiliation: Epidemiology and Biostatistics Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.affiliation: Hematology Unit, San Gerardo Hospital, Monza, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Longoni
authors.affiliation: Pediatric Hematology and Oncology Unit, A.R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli, Palermo, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Farruggia
authors.affiliation: Hematology Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dufour
authors.affiliation: Hematology Unit, Istituto Giannina Gaslini, Genoa, Italy. Electronic address: enricocappelli@ospedale-gaslini.ge.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cappelli
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002648:Child; D004920:Erythropoiesis; D005199:Fanconi Anemia / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases