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Blood, 1 July 2005, Vol. 106, No. 1, pp. 247-253.
Prepublished online as a Blood First Edition Paper on March 8, 2005; DOI 10.1182/blood-2004-12-4649.
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Submitted December 6, 2004
Accepted February 26, 2005
Aberrant mitochondrial iron distribution and maturation arrest characterizes early erythroid precursors in low-risk myelodysplastic syndromes
Ramin Tehranchi*, Rosangela Invernizzi, Alf Grandien, Boris Zhivotovsky, Bengt Fadeel, Ann-Mari Forsblom, Erica Travaglino, Jan Samuelsson, Robert Hast, Lars Nilsson, Mario Cazzola, Rolf Wibom, and Eva Hellstrom-Lindberg
Department of Medicine, Division of Hematology, Karolinska University Hospital Huddinge, Stockholm, Sweden
Department of Hematology and Department of Internal Medicine, University of Pavia Medical School and IRCCS Policlinico S Matteo, Pavia, Italy
Department of Medicine, Center of Infectious Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden
Institute of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institutet, Stockholm, Sweden
Department of Medicine, Southern Hospital, Karolinska Institutet, Stockholm, Sweden
Department of Internal Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, and Department of Hematology, Lund University Hospital, Lund University, Lund, Sweden
Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
* Corresponding author; email: Ramin.Tehranchi{at}medhs.ki.se.
Early erythroblasts from patients with refractory anemia (RA) and RA with ringed sideroblasts (RARS) show constitutive mitochondrial release of cytochrome c. Moreover, mature erythroblasts in RARS, but not in RA, display aberrant accumulation of mitochondrial ferritin (MtF). We analyzed cytochrome c release, MtF expression, and gene expression during erythroid differentiation in bone marrow cells from myelodysplastic syndrome (MDS) patients and healthy controls. Whereas none or few cultured erythroid cells from normal individuals and RA patients expressed MtF, those from RARS patients showed MtF expression at an early stage, when cells were CD34+ and without morphological signs of erythroid differentiation. The proportion of RARS erythroblasts that were MtF+ increased further upon in vitro maturation. Moreover, a significant over-expression of mRNA encoding cytochrome c, and pro-apoptotic Bid and Bax, was seen in freshly isolated cells from MDS patients. Genes involved in erythroid differentiation were also dysregulated in MDS cells. Importantly, GATA-1 expression increased during normal erythroid maturation, but remained low in MDS cultures, indicating a block of erythroid maturation at the transcriptional level. In conclusion, aberrant MtF expression in RARS erythroblasts occurs at a very early stage of erythroid differentiation and is paralleled by an up-regulation of genes involved in this process.
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