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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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NEOPLASIA
Aberrant mitochondrial iron distribution and maturation arrest characterize 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 Hellström-Lindberg
From the Department of Medicine, Division of Hematology, and the Center of Infectious Medicine, and the Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden; the Department of Hematology and Department of Internal Medicine, University of Pavia Medical School and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S Matteo, Pavia, Italy; the Institute of Environmental Medicine, Division of Toxicology and Division of Molecular Toxicology, the Department of Medicine, Southern Hospital, Karolinska Institutet, Stockholm, Sweden; the Department of Internal Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; and the Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University and Department of Hematology, Lund University Hospital, Lund, Sweden.
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 healthy individuals and RA patients expressed MtF, those from RARS patients showed MtF expression at an early stage, when cells were CD34+ and without morphologic signs of erythroid differentiation. The proportion of RARS erythroblasts that were MtF+ increased further upon in vitro maturation. Moreover, a significant overexpression of mRNA encoding cytochrome c, and proapoptotic 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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