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Haematologica. 2015 Jun;100(6):720-9. doi: 10.3324/haematol.2014.114488. Epub 2015 Mar 20.

The heme exporter Flvcr1 regulates expansion and differentiation of committed erythroid progenitors by controlling intracellular heme accumulation.

Author information

1
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy.
2
Tisch Cancer Institute and Black Family Stem Cell Institute, Division of Hematology and Medical Oncology and Departments of Developmental and Regenerative Biology and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Department of Veterinary Science, University of Turin, Italy.
4
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy Vesalius Research Center, VIB-KUL, Leuven, Belgium.
5
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Turin, Italy emanuela.tolosano@unito.it.

Abstract

Feline leukemia virus subgroup C receptor 1 (Flvcr1) encodes two heme exporters: FLVCR1a, which localizes to the plasma membrane, and FLVCR1b, which localizes to mitochondria. Here, we investigated the role of the two Flvcr1 isoforms during erythropoiesis. We showed that, in mice and zebrafish, Flvcr1a is required for the expansion of committed erythroid progenitors but cannot drive their terminal differentiation, while Flvcr1b contributes to the expansion phase and is required for differentiation. FLVCR1a-down-regulated K562 cells have defective proliferation, enhanced differentiation, and heme loading in the cytosol, while FLVCR1a/1b-deficient K562 cells show impairment in both proliferation and differentiation, and accumulate heme in mitochondria. These data support a model in which the coordinated expression of Flvcr1a and Flvcr1b contributes to control the size of the cytosolic heme pool required to sustain metabolic activity during the expansion of erythroid progenitors and to allow hemoglobinization during their terminal maturation. Consistently, reduction or increase of the cytosolic heme rescued the erythroid defects in zebrafish deficient in Flvcr1a or Flvcr1b, respectively. Thus, heme export represents a tightly regulated process that controls erythropoiesis.

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PMID:
25795718
PMCID:
PMC4450617
DOI:
10.3324/haematol.2014.114488
[Indexed for MEDLINE]
Free PMC Article
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