Investigating the interplay between iron (overload) and erythropoiesis in rare hereditary anemias.

The group of rare hereditary anemias (RHA) includes a large variety of defects
of red blood cells and erythropoiesis, including hemoglobinopathies,
erythrocyte enzyme defects and hypoplastic anemias, such as Diamond Blackfan
anemia (DBA). Despite very disease-specific manifestations, this group of
disorders also shares important clinical, hematological and biochemical
features, including ineffective erythropoiesis, and disturbed iron homeostasis.
In RHA, iron overload is a common and severe complication, inducing severe
organ damage, including liver fibrosis, heart failure, and endocrine
dysfunction. In addition, iron excess induces reactive oxygen species
(ROS)-mediated toxicity to bone marrow stromal cells, further worsening the
effects of chronic anemia. Surprisingly, whereas the regulation of iron
homeostasis is obviously crucial for patients with severe chronic anemias and
iron overload, there is still little understanding concerning disease-specific
regulators of iron homeostasis and their role in ineffective erythropoiesis.
Mechanisms that have been suggested include differential regulation of reactive
oxygen species (ROS), and more recently, ferroptosis, an alternative form of
regulated cell death, characterized by the accumulation of lipid peroxidation
products and lethal ROS, and functionally directly linked to iron metabolism.
Together, it seems conceivable that manipulation of the hepcidin pathway
(regulating iron uptake and recycling), and targeting ferroptosis in RHA could
improve iron hemostasis and consequently erythropoiesis. In order to
investigate this and to increase our understanding of the functional interplay
between iron and erythropoiesis in RHA, a novel explorative approach is needed.

Investigate regulators of (disturbed) iron homeostasis and cellular
determinants of iron overload in RHA. to decipher crucial elements of the
crosstalk between iron metabolism and erythropoiesis

This study is a longitudinal observational study in which in vitro assays will
be performed on peripheral blood samples (and stored bone marrow samples)
collected at routine visits at the outpatients* clinic.

Burden: In this study we will collect additional blood samples for in vitro
studies. Therefore, the burden will be minimal.
There will be no interventions as the collection of blood for this study will
be combined with routine venipunctures during their visit to the outpatient
clinic. This implicates there will also be no additional risks.


Benefit: The clinical consequences of chronic anemia and iron overload are
important issues during long term clinical management of patients with RHA.
Therefore, a better understanding of the mechanisms driving disturbed iron
homeostasis, and the effects on erythropoiesis are crucial. This study will
contribute to the identification of novel therapeutic targets to improve our
clinical management of iron overload and ineffective erythropoiesis in RHA.