Ineffective erythropoiesis in sickle cell disease: new insights and future implications.

ABSTRACT

PURPOSE OF REVIEW Sickle cell disease (SCD) is a hemolytic anemia caused by a point mutation in the ß globin gene leading to the expression of an abnormal hemoglobin (HbS) that polymerizes under hypoxic conditions driving red cell sickling. Circulating red cells have been extensively characterized in SCD, as their destruction and removal from peripheral blood are the major contributors to anemia. However, few reports showed cellular abnormalities during erythropoiesis in SCD, suggesting that anemia could also be influenced by defects of central origin. RECENT FINDINGS: El Hoss et al. demonstrated ineffective erythropoiesis (IE) in SCD and deciphered the molecular mechanism underlying cell death during the hemoglobin synthesis phase of terminal differentiation. They showed that HbS polymerization induces apoptosis of differentiating erythroblasts and that fetal hemoglobin rescues these cells through its antipolymerization function. SUMMARY: IE is the major cause of anemia in ß-thalassemia patients, and it is generally surmised that it contributes little to anemia of SCD. Recent reports demonstrate the occurrence of IE in SCD patients and show important alterations in the hematopoietic and erythroid niches, both in SCD patients and in the humanized Townes SCD mouse model. This implies that therapeutic strategies initially designed to improve red cell survival in the circulation of SCD patients would also positively impact erythropoiesis and bone marrow cellularity.