P38 mitogen-activated protein kinase inhibition enhances invitro erythropoiesis of Fanconi anemia, complementation group A-deficient bonemarrow cells

Johanna Svahn, Tiziana Lanza, Keaney Rathbun, Grover Bagby, Silvia Ravera, Fabio Corsolini, Angela Pistorio, Daniela Longoni, Piero Farruggia, Carlo Dufour, Enrico Cappelli

    Research output: Contribution to journalArticle

    8 Scopus citations

    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. 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.

    Original languageEnglish (US)
    Pages (from-to)295-299
    Number of pages5
    JournalExperimental hematology
    Volume43
    Issue number4
    DOIs
    StatePublished - Apr 1 2015

    ASJC Scopus subject areas

    • Molecular Biology
    • Hematology
    • Genetics
    • Cell Biology
    • Cancer Research

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  • Cite this

    Svahn, J., Lanza, T., Rathbun, K., Bagby, G., Ravera, S., Corsolini, F., Pistorio, A., Longoni, D., Farruggia, P., Dufour, C., & Cappelli, E. (2015). P38 mitogen-activated protein kinase inhibition enhances invitro erythropoiesis of Fanconi anemia, complementation group A-deficient bonemarrow cells. Experimental hematology, 43(4), 295-299. https://doi.org/10.1016/j.exphem.2014.11.010