title: Transfusion-independent β(0)-thalassemia after bone marrow transplantation failure: proposed involvement of high parental HbF and an epigenetic mechanism.
abstract: Currently, bone marrow transplantation is the only curative treatment for β-thalassemia and sickle cell disease. In rare cases, sustained and full fetal hemoglobin production was observed in patients after failure of bone marrow transplantation. This rendered the patients transfusion-free, despite genetic disease and transplant rejection. The mechanisms underlying this phenomenon remain unexplored. We have studied a trio (father-mother-child) in which the affected child became transfusion-independent after rejection of an allogeneic bone marrow graft. Remarkably, we found that his non-thalassemic mother also expressed unusually high levels of γ-globin. High HbF in one of the parents may therefore be of prognostic value in these rare cases. Genotyping of the HBB locus and the HbF quantitative trait loci HBS1L-MYB, KLF1 and BCL11A, and protein expression analysis of KLF1 and BCL11A, failed to explain the increased HbF levels, indicating that an as yet unidentified HbF modifier locus may be involved. We hypothesize that epigenetic events brought about by the transplantation procedure allow therapeutic levels of HbF expression in the child. Potential implications of our observations for reactivation of γ-globin expression and interpretation of the French globin gene therapy case are discussed.
authors.affiliation: Mediterranean Institute of Hematology, Policlinic of Tor Vergata Oxford Avenue, 00152 Rome, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Paciaroni
authors.affiliation: Mediterranean Institute of Hematology, Policlinic of Tor Vergata Oxford Avenue, 00152 Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Lucarelli
authors.affiliation: Istituto Superiore di Sanità Viale Regina Elena 299, 00161 - Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Martelli
authors.affiliation: Istituto Superiore di Sanità Viale Regina Elena 299, 00161 - Rome, Italy ; Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine One Gustave L. Levy Place, Box 1079, New York, NY 10029, USA.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Dr Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta Msida, MSD2090, Malta ; Department of Cell Biology, Erasmus MC P.O. box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Joseph
authors.initials: J
authors.lastname: Borg
authors.affiliation: Department of Cell Biology, Erasmus MC P.O. box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Nynke
authors.initials: N
authors.lastname: Gillemans
authors.affiliation: Department of Cell Biology, Erasmus MC P.O. box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Thamar B
authors.initials: TB
authors.lastname: van Dijk
authors.affiliation: Department of Cell Biology, Erasmus MC P.O. box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Sjaak
authors.initials: S
authors.lastname: Philipsen
keywords: BCL11A; HBB; HbF; KLF1; MYB; bone marrow transplantation; epigenetics; transfusion-independence; β-thalassemia