Patricia A. Oneal

High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin

In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 ± 50 pg/ml. In comparison, individuals with β-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 ± 9,600 pg/ml; range 4,800–248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.

Imatinib-Responsive Hypereosinophilia in a Patient with B Cell ALL

Hypereosinophilia is a rare presenting sign of acute lymphocytic leukemia. A 29-year-old male was diagnosed with idiopathic hypereosinophilic syndrome with respiratory symptoms. Although his peripheral blood eosinophilia decreased in response to treatment with imatinib mesylate, a follow-up bone marrow showed a diffuse infiltrate of myeloperoxidase-negative blasts. He was subsequently diagnosed with CD10 positive precursor B lymphoblastic leukemia. This case underscores the importance of follow-up bone marrow examination in patients who demonstrate imatinib mesylate-responsive eosinophilia.