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Exp Hematol. 2015 Apr;43(4):295-9. doi: 10.1016/j.exphem.2014.11.010. Epub 2014 Dec 19.

p38 Mitogen-activated protein kinase inhibition enhances in vitro erythropoiesis of Fanconi anemia, complementation group A-deficient bone marrow cells.

Author information

1
Hematology Unit, Istituto Giannina Gaslini, Genoa, Italy.
2
Oregon Health & Science University, Portland, OR, United States.
3
DIFAR-Biochemistry Laboratory, Department of Pharmacology, University of Genoa, Genoa, Italy.
4
Laboratorio Diagnosi Pre e Postnatale Malattie Metaboliche, Istituto Giannina Gaslini, Genoa, Italy.
5
Epidemiology and Biostatistics Unit, Istituto Giannina Gaslini, Genoa, Italy.
6
Hematology Unit, San Gerardo Hospital, Monza, Italy.
7
Pediatric Hematology and Oncology Unit, A.R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli, Palermo, Italy.
8
Hematology Unit, Istituto Giannina Gaslini, Genoa, Italy. Electronic address: enricocappelli@ospedale-gaslini.ge.it.

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.

PMID:
25534205
DOI:
10.1016/j.exphem.2014.11.010
[Indexed for MEDLINE]

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