TY - JOUR
T1 - P38 mitogen-activated protein kinase inhibition enhances invitro erythropoiesis of Fanconi anemia, complementation group A-deficient bonemarrow cells
AU - Svahn, Johanna
AU - Lanza, Tiziana
AU - Rathbun, Keaney
AU - Bagby, Grover
AU - Ravera, Silvia
AU - Corsolini, Fabio
AU - Pistorio, Angela
AU - Longoni, Daniela
AU - Farruggia, Piero
AU - Dufour, Carlo
AU - Cappelli, Enrico
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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. Exvivo 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.
AB - 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. Exvivo 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.
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U2 - 10.1016/j.exphem.2014.11.010
DO - 10.1016/j.exphem.2014.11.010
M3 - Article
C2 - 25534205
AN - SCOPUS:84925340044
VL - 43
SP - 295
EP - 299
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 4
ER -