Bone marrow cell gene expression profiles characterize several mechanisms of action of hydroxyurea in sickle cell anemia

摘要

Sickling of red blood cells in sickle cell anemia (SCA) is a consequence of a single amino acid substitution at codon 6 of the adult beta-globin gene, producing abnormal hemoglobin S (HbS). High levels of fetal hemoglobin (HbF) have been shown to ameliorate the clinical symptoms of SCA patients due to its ability to inhibit the polymerization of HbS. Hydroxyurca (HU), a ribonucleotide reductase inhibitor largely used for chemotherapy of myeloproliferative malignancies, increases HbF levels and improves clinical symptoms in SCA patients, although the mechanisms by which HU functions remains unclear. To delineate the molecular pathways that may be involved in the action of HU, two gene expression profiles were obtained from bone marrow cells (BMCs) of an SCA patient, before and after HU treatment, using Serial Analysis of Gene Expression (SAGE). A total of 45,014 tags were analyzed before HU treatment and 49,814 tags after 90 days of HU treatment; 15,358 and 16,507 unique tags were identified, respectively. Among them, approximately 76% of the unique tags from both profiles matched known genes or ORFs in the human genome, and 24% corresponded to tags that did not match sequences within the current reference version of the human genome. These may represent novel transcripts. In a comparison of both profiles, 147 tags represented differentially expressed transcripts at a statistically significant level (P<0.01).