Growth differentiation factor 15 in erythroid health and disease

Abstract

Purpose of review: Growth differentiation factor 15 (GDF15) was identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. This review addresses the regulation, expression and potential functions of GDF15 in the context of erythroid biology.

Recent findings: GDF15 expression during late erythroid differentiation was discovered as part of an erythroblast transcriptome project. As GDF15 expression is associated with cellular stress or apoptosis, further investigation of the cytokine was focused upon its involvement in ineffective erythropoiesis. Remarkably high serum levels were detected in patients with thalassemia syndromes, congenital dyserythropoiesis and some acquired sideroblastic anemias. High-level GDF15 expression is not a feature of normal erythropoiesis, or erythroid recovery after bone-marrow transplantation. As GDF15 is a transforming growth factor-beta superfamily member, it was investigated as an effector of ineffective erythropoiesis that suppresses hepcidin expression despite iron overloading.

Summary: In contrast to the low levels of GDF15 expressed during normal erythropoiesis, ineffective erythropoiesis causes high-level expression of GDF15. In patients with thalassemia and related anemias, GDF15 expression may contribute to iron overloading or other features of the disease phenotype.

Figure 1. Genomic structure and transcription for protein production of matured GDF15

The diagram shows GDF15 gene structure with several transcription factors binding sites in the promoter region. GDF15 is synthesized from two exons, and dimerized with disulfide bonds, then cleaved at RXXR site to form C-terminal mature GDF15 protein. H6D denotes a single-nucleotide polymorphism at position 6 of the mature protein resulting in histidine to aspartic acid substitution.

Figure 2. GDF15 concentrations in human blood from healthy volunteers and several hematological diseases

The individual data points represent GDF15 concentrations from healthy volunteers (HV; n = 37), sickle cell anemia (SS; n = 13), thalassemia trait (Thal-trait; n = 12), α-thalassemia (α-Thal; n = 20), β-thalassemia (β-Thal; n = 40) [23], and congenital dyserythropoietic anemia type I (CDAI; n = 17) [28]. The lines represent the maximum and minimum concentrations from patients with refractory anemia with ring sideroblasts (RARS, n = 20) [31] and pyruvate kinase deficiency (PKD, n = 22) [34]. Bars show the mean of GDF15 concentrations.

Figure 3. GDF15 expression in bone marrow from a patient with thalassemia

Brown coloration marks GDF15 present in late-stage erythroblasts in thalassemia bone marrow. No similar staining was noted in bone marrow from a healthy volunteer.

Figure 4. Model of iron homeostasis in patients with ineffective erythropoiesis

With permission from reference