Unravelling the importance of Iron Regulatory Proteins for Granulopoiesis

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Research in the past few years uncovered the critical importance of metabolism for the control of stem cell behavior and lineage specification in the hematopoietic system. While much of the focus has been on intermediary and energy metabolism, the role of trace elements such as iron in hematopoietic cell fate decisions remains ill understood. In mammals, cellular iron homeostasis is orchestrated posttranscriptionally by the iron regulatory proteins (IRP)-1 and -2, which control the fate of mRNAs encoding key iron metabolism proteins in the cell. We have generated a novel mouse model enabling acute disruption of IRP function in the entire body, and discovered that IRPs are required for maintaining physiological levels of neutrophils during adulthood. A thorough analysis of the hematopoietic system revealed marked defects in neutrophil differentiation in the bone marrow, with accumulation of progenitor cells that fail to progress normally towards the granulocytic lineage and instead give rise to seemingly “immature” neutrophils. Based on reciprocal bone marrow transplantation experiments in vivo and an ex vivo cell culture model, we could demonstrate that IRPs support neutrophil differentiation in a cell intrinsic manner. These results uncover a previously unrecognized role for the IRPs in adult hematopoiesis. We now propose to define the functional and molecular characteristics of IRP-deficient neutrophils, and investigate how precisely the IRPs support normal neutropoiesis. We will first assess the morphology and assay key functions of “immature” neutrophils lacking IRP expression. In parallel, we will profile the transcriptome of hematopoietic cells at different stages of neutrophil differentiation. Combined with gene/functional enrichment clustering approaches, this will help us delineate which cellular pathways are primarily affected in IRP deficiency and thus potentially important for the neutropoietic functions of the IRPs. We will then use gene rescue experiments ex vivo and in vivo gene therapy to determine which of the candidate pathways links IRP function to neutropoiesis. With this work we wish to unveil new facets of a central homeostatic control system in the cell and enhance our understanding of the role of metabolism in hematopoiesis.