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Coordinate expression of heme and globin is essential for effective erythropoiesis.

ABSTRACT: Erythropoiesis requires rapid and extensive hemoglobin production. Heme activates globin transcription and translation; therefore, heme synthesis must precede globin synthesis. As free heme is a potent inducer of oxidative damage, its levels within cellular compartments require stringent regulation. Mice lacking the heme exporter FLVCR1 have a severe macrocytic anemia; however, the mechanisms that underlie erythropoiesis dysfunction in these animals are unclear. Here, we determined that erythropoiesis failure occurs in these animals at the CFU-E/proerythroblast stage, a point at which the transferrin receptor (CD71) is upregulated, iron is imported, and heme is synthesized--before ample globin is produced. From the CFU-E/proerythroblast (CD71(+) Ter119(-) cells) stage onward, erythroid progenitors exhibited excess heme content, increased cytoplasmic ROS, and increased apoptosis. Reducing heme synthesis in FLVCR1-defient animals via genetic and biochemical approaches improved the anemia, implying that heme excess causes, and is not just associated with, the erythroid marrow failure. Expression of the cell surface FLVCR1 isoform, but not the mitochondrial FLVCR1 isoform, restored normal rbc production, demonstrating that cellular heme export is essential. Together, these studies provide insight into how heme is regulated to allow effective erythropoiesis, show that erythropoiesis fails when heme is excessive, and emphasize the importance of evaluating Ter119(-) erythroid cells when studying erythroid marrow failure in murine models.

SUBMITTER: Doty RT

PROVIDER: S-EPMC4665774 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Coordinate expression of heme and globin is essential for effective erythropoiesis.

Doty Raymond T RT Phelps Susan R SR Shadle Christina C Sanchez-Bonilla Marilyn M Keel Siobán B SB Abkowitz Janis L JL

The Journal of clinical investigation 20151109 12

Erythropoiesis requires rapid and extensive hemoglobin production. Heme activates globin transcription and translation; therefore, heme synthesis must precede globin synthesis. As free heme is a potent inducer of oxidative damage, its levels within cellular compartments require stringent regulation. Mice lacking the heme exporter FLVCR1 have a severe macrocytic anemia; however, the mechanisms that underlie erythropoiesis dysfunction in these animals are unclear. Here, we determined that erythrop ...[more]

PMID: 26551679

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Project description:The anti-apoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1, A1, BCL-W) counteract apoptotic signals emerging during development and under stress conditions, and are thus essential for the survival of every cell. While the "BCL-2 addiction" of different cell types is well described in mouse models, there is only limited information available on the role of different anti-apoptotic BCL-2 proteins in a given human cell type. Here we characterize the role of BCL-XL for survival and function of human hematopoietic cells, with the aim to predict hematological side effects of novel BCL-XL-inhibiting BH3-mimetics and to identify hematological malignancies potentially responsive to such inhibitors. Earlier clinical studies have shown that the combined BCL-2/BCL-XL/BCL-W inhibitor, Navitoclax (ABT-263) induces severe thrombocytopenia caused by direct platelet demise and counteracted by increased megakaryopoiesis. In contrast, murine studies have reported important contribution of BCL-XL to survival of late erythroid cells and megakaryocytes. Using lentiviral knockdown, we show that the roles of BCL-XL for human hematopoietic cells are much more pronounced than expected from murine data and clinical trials. Efficient genetic or chemical BCL-XL inhibition resulted in significant loss of human erythroid cells beginning from very early stages of erythropoiesis, and in a reduction of megakaryocytes. Most importantly, BCL-XL deficient human hematopoietic stem cells and multipotent progenitors were reduced in numbers, and they showed a severely impaired capacity to engraft in mice during xenotransplantation. BCL-XL deficiency was fully compensated by BCL-2 overexpression, however, loss of its antagonist BIM did not result in any rescue of human erythroid or stem and progenitor cells. We thus conclude that novel and specific BCL-XL inhibitors might be efficient to treat malignancies of erythroid or megakaryocytic origin, such as polycythemia vera, acute erythroid leukemia, essential thrombocytosis or acute megakaryocytic leukemia. At the same time, it can be expected that they will have more severe hematological side effects than Navitoclax.

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Coordinate expression of heme and globin is essential for effective erythropoiesis.

Publications

Coordinate expression of heme and globin is essential for effective erythropoiesis.

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