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Low Iron Promotes Megakaryocytic Commitment of Megakaryocytic-Erythroid Progenitors in Humans and Mice

Juliana Xavier-Ferrucio, Vanessa Scanlon, Xiuqi Li, Ping-Xia Zhang, Larisa Lozovatsky, Nadia Ayala-Lopez, Toma Tebaldi, Stephanie Halene, Chang Cao, Mark D. Fleming, Karin E. Finberg and Diane S. Krause

Key Points

  • Low iron in the environment promotes megakaryocytic commitment of MEP.

  • MEP from mice with iron deficiency anemia show decreased proliferation and decreased ERK phosphorylation.

Abstract

The mechanisms underlying thrombocytosis in patients with iron deficiency anemia remain unknown. Here, we present findings that support the hypothesis that low iron biases the commitment of Megakaryocytic-Erythroid Progenitors (MEP) toward the megakaryocytic (Mk) lineage in both human and mouse. In MEP of Transmembrane serine protease 6 knockout (Tmprss6-/-) mice, which exhibit iron deficiency anemia and thrombocytosis, we observed a Mk bias, decreased labile iron, and decreased proliferation relative to wild-type (WT) MEP. Bone marrow transplantation assays suggest that systemic iron deficiency, rather than a local role for Tmprss6-/-in hematopoietic cells, contributes to the MEP lineage commitment bias observed in Tmprss6-/-mice. Non-transgenic mice with acquired iron deficiency anemia also show thrombocytosis and Mk biased MEP. Gene expression analysis reveals that mRNAs encoding genes involved in metabolic, VEGF, and ERK pathways are enriched in Tmprss6-/-versus WT MEP. Corroborating our findings from the murine models of iron deficiency anemia, primary human MEP exhibit decreased proliferation and Mk-biased commitment after knockdown of Transferrin Receptor 2, a putative iron sensor. Signal transduction analyses reveal that both human and murine MEP have lower levels of phospho-ERK1/2 in iron deficient conditions compared to controls. These data are consistent with a model in which low iron in the marrow environment affects MEP metabolism, attenuates ERK signaling, slows proliferation, and biases MEP toward Mk lineage commitment.

  • Submitted October 18, 2018.
  • Revision received August 22, 2019.
  • Accepted August 9, 2019.