title: Evidence for ineffective erythropoiesis in severe sickle cell disease.
abstract: Peripheral destruction of sickled erythrocytes is a cardinal feature of sickle cell disease (SCD). Less well established is the potential contribution of ineffective erythropoiesis to the pathophysiology of this hemoglobinopathy. Since patients with SCD frequently develop mixed hematopoietic chimerism after allogeneic nonmyeloablative stem cell transplantation, we used this opportunity to directly compare the differentiation and survival of SCD and donor-derived erythropoiesis in vivo. Donor and recipient erythropoiesis was compared in 4 patients with SCD and 4 without SCD who developed stable mixed hematopoietic chimerism following transplant. Molecular analysis of chimerism in peripheral blood and bone marrow demonstrated higher expression of donor-derived beta-globin RNA relative to the level of donor-derived genomic DNA in patients with SCD. Analysis of chimerism in immature (glycophorin A-positive [GYPA(+)], CD71(hi)) and mature (GYPA(+), CD71(neg)) erythroblasts confirmed the intramedullary loss of SS erythroblasts with progressive maturation. In patients with SCD, relative enrichment of donor erythroid precursors began to appear at the onset of hemoglobinization. Ineffective erythropoiesis of homozygous hemoglobin S (SS) progenitors thus provides a maturation advantage for homozygous hemoglobin A (AA) or heterozygous hemoglobin S/hemoglobin A (SA) donor erythroid precursor cells that results in greater donor contribution to overall erythropoiesis following stem-cell transplantation and improvement of clinical disease.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02115, USA. cwu@partners.org
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.forename: Lakshamanan
authors.initials: L
authors.lastname: Krishnamurti
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Melinda
authors.initials: M
authors.lastname: Biernacki
authors.forename: Shelby
authors.initials: S
authors.lastname: Rogers
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhang
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D004900:Erythroblasts / Q000378:metabolism* / Q000473:pathology; D004920:Erythropoiesis; D005260:Female; D006021:Glycophorins; D006461:Hemolysis; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D011990:Receptors, Transferrin / Q000378:metabolism; D020127:Recovery of Function; D012795:Sialoglycoproteins; D033581:Stem Cell Transplantation / Q000379:methods; D014019:Tissue Donors; D018183:Transplantation Chimera / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; C409972:GYPA protein, human; D006021:Glycophorins; D008562:Membrane Glycoproteins; D011990:Receptors, Transferrin; D012795:Sialoglycoproteins