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

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
Pages (from-to)295-299
Number of pages5
JournalExperimental Hematology
Volume43
Issue number4
DOIs
Publication statusPublished - Apr 1 2015

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Fanconi Anemia
Erythropoiesis
p38 Mitogen-Activated Protein Kinases
Stem Cells
Monocytes
resiquimod
Toll-Like Receptor 7
Erythroid Precursor Cells
Toll-Like Receptor 4
Hematopoiesis
Lipopolysaccharides
Clone Cells
Tumor Necrosis Factor-alpha
Bone Marrow
Cytokines
Ligands
Cell Line
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology
  • Medicine(all)

Cite this

P38 mitogen-activated protein kinase inhibition enhances invitro erythropoiesis of Fanconi anemia, complementation group A-deficient bonemarrow cells. / Svahn, Johanna; Lanza, Tiziana; Rathbun, Keaney; Bagby, Grover; Ravera, Silvia; Corsolini, Fabio; Pistorio, Angela; Longoni, Daniela; Farruggia, Piero; Dufour, Carlo; Cappelli, Enrico.

In: Experimental Hematology, Vol. 43, No. 4, 01.04.2015, p. 295-299.

Research output: Contribution to journalArticle

Svahn, Johanna ; Lanza, Tiziana ; Rathbun, Keaney ; Bagby, Grover ; Ravera, Silvia ; Corsolini, Fabio ; Pistorio, Angela ; Longoni, Daniela ; Farruggia, Piero ; Dufour, Carlo ; Cappelli, Enrico. / P38 mitogen-activated protein kinase inhibition enhances invitro erythropoiesis of Fanconi anemia, complementation group A-deficient bonemarrow cells. In: Experimental Hematology. 2015 ; Vol. 43, No. 4. pp. 295-299.
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