Hydroxycarbamide alters erythroid gene expression in children with sickle cell anaemia
Jonathan M Flanagan, Shirley Steward, Thad A Howard, Nicole A Mortier, Amy C Kimble, Banu Aygun, Jane S Hankins, Geoffrey A Neale, Russell E Ware, Jonathan M Flanagan, Shirley Steward, Thad A Howard, Nicole A Mortier, Amy C Kimble, Banu Aygun, Jane S Hankins, Geoffrey A Neale, Russell E Ware
Abstract
Sickle cell anaemia (SCA) is a severe debilitating haematological disorder associated with a high degree of morbidity and mortality. The level of fetal haemoglobin (HbF) is well-recognized as a critical laboratory parameter: lower HbF is associated with a higher risk of vaso-occlusive complications, organ damage, and early death. Hydroxycarbamide treatment can induce HbF, improve laboratory parameters, and ameliorate clinical complications of SCA but its mechanisms of action remain incompletely defined and the HbF response is highly variable. To identify pathways of hydroxycarbamide activity, we performed microarray expression analyses of early reticulocyte RNA obtained from children with SCA enrolled in the HydroxyUrea Study of Long-term Effects (NCT00305175) and examined the effects of hydroxycarbamide exposure in vivo. Hydroxycarbamide affected a large number of erythroid genes, with significant decreases in the expression of genes involved in translation, ribosome assembly and chromosome organization, presumably reflecting the daily cytotoxic pulses of hydroxycarbamide. Hydroxycarbamide also affected expression of numerous genes associated with HbF including BCL11A, a key regulator of baseline HbF levels. Together, these data indicate that hydroxycarbamide treatment for SCA leads to substantial changes in erythroid gene expression, including BCL11A and other potential signalling pathways associated with HbF induction.
© 2012 Blackwell Publishing Ltd.
Source: PubMed