Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes.
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.
Tehranchi
Ramin
R
Department of Medicine, Division of Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden. ramin.tehranchi@medhs.ki.se
Invernizzi
Rosangela
R
Grandien
Alf
A
Zhivotovsky
Boris
B
Fadeel
Bengt
B
Forsblom
Ann-Mari
AM
Travaglino
Erica
E
Samuelsson
Jan
J
Hast
Robert
R
Nilsson
Lars
L
Cazzola
Mario
M
Wibom
Rolf
R
Hellström-Lindberg
Eva
E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000756:Anemia, Sideroblastic / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004900:Erythroblasts / Q000378:metabolism / Q000473:pathology; D050981:Erythroid-Specific DNA-Binding Factors; D005293:Ferritins / Q000378:metabolism; D050982:GATA1 Transcription Factor; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006454:Hemoglobins / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009190:Myelodysplastic Syndromes / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D006023:Glycoproteins; D006454:Hemoglobins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D016179:Granulocyte Colony-Stimulating Factor; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D005293:Ferritins; C020622:hemoglobin B; D007501:Iron