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Refractory anaemia with ring sideroblasts (RARS) is characterized by anaemia, erythroid apoptosis, cytochrome c release and mitochondrial ferritin accumulation. Granulocyte-colony-stimulating factor (G-CSF) inhibits the first three of these features in vitro and in vivo. To dissect the molecular mechanisms underlying the RARS phenotype and anti-apoptotic effects of G-CSF, erythroblasts generated from normal (NBM) and RARS marrow CD34(+) cells were cultured +/-G-CSF and subjected to gene expression analysis (GEP). Several erythropoiesis-associated genes that were deregulated in RARS CD34(+) cells showed normal expression in erythroblasts, underscoring the importance of differentiation-specific GEP. RARS erythroblasts showed a marked deregulation of several pathways including apoptosis, DNA damage repair, mitochondrial function and the JAK/Stat pathway. ABCB7, transporting iron from mitochondria to cytosol and associated with inherited ring sideroblast formation was severely suppressed and expression decreased with differentiation, while increasing in NBM cultures. The same pattern was observed for the mitochondrial integrity gene MFN2. Other downregulated key genes included STAT5B, HSPA5, FANCC and the negative apoptosis regulator MAP3K7. Methylation status of key downregulated genes was normal. The mitochondrial pathway including MFN2 was significantly modified by G-CSF, and several heat shock protein genes were upregulated, as evidence of anti-apoptotic protection of erythropoiesis. By contrast, G-CSF had no effect on iron-transport or erythropoiesis-associated genes.

Original publication

DOI

10.1111/j.1365-2141.2010.08174.x

Type

Journal article

Journal

Br J Haematol

Publication Date

06/2010

Volume

149

Pages

844 - 854

Keywords

Aged, Anemia, Refractory, Anemia, Sideroblastic, Apoptosis, Cell Differentiation, Cell Survival, Cells, Cultured, Erythroblasts, Erythroid Precursor Cells, Erythropoiesis, Female, Gene Expression Profiling, Gene Expression Regulation, Granulocyte Colony-Stimulating Factor, Humans, Iron, Male, Middle Aged, Mitochondria, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction