Gene expression profiling of erythroblasts from refractory anaemia with ring sideroblasts (RARS) and effects of G-CSF

Maryam Nikpour, Andrea Pellagatti, Anquan Liu, Mohsen Karimi, Luca Malcovati, Vladimir Gogvadze, Ann Mari Forsblom, James S. Wainscoat, Mario Cazzola, Boris Zhivotovsky, Alf Grandien, Jacqueline Boultwood, Eva Hellström-Lindberg

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageEnglish
Pages (from-to)844-854
Number of pages11
JournalBritish Journal of Haematology
Volume149
Issue number6
DOIs
Publication statusPublished - Jun 2010

Keywords

  • ABCB7
  • Gene expression profiling
  • MFN2
  • Pathway analyses
  • Refractory anaemia with ring sideroblasts

ASJC Scopus subject areas

  • Hematology

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