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

Maryam Nikpour (1) , Andrea Pellagatti (2) , Anquan Liu (1) , Mohsen Karimi (3) , Luca Malcovati (4) , Vladimir Gogvadze (5) , Ann-Mari Forsblom (1) , Jim Wainscoat (6) , Mario Cazzola (7) , Boris Zhivotovsky (5) , Alf Grandien (8) , Jackie Boultwood (9) , Eva Hellström-Lindberg (1)

1 Department of Medicine, Division of Hematology
2 NDCLS
3 Department of Medicine, Division of Hematology
4 Division of Hematology
5 IMM - The Institute of Environmental Medicine [Stockholm]
6 NDCLS
7 Division of Hematology
8 Department of medicine [Stockholm]
9 LRF Molecular & Cytogenetic Haem. Unit

RARS is characterized by anaemia, erythroid apoptosis, cytochrome c release and mitochondrial ferritin accumulation. Granulocyte-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 subject to gene expression analysis (GEP). Several erythropoiesis-associated genes 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 down-regulated key genes included STAT5b, HSP5A, FANCC, and the negative apoptosis regulator MAP3K7. Methylation status of key down-regulated genes was normal. The mitochondrial pathway including MFN2 was significantly modified by G-CSF, and several heat shock protein genes were up-regulated, as evidence of anti-apoptotic protection of erythropoiesis. By contrast, G-CSF had no effect on iron-transport or erythropoiesis-associated genes.

Mots clés: Medicine

Maryam Nikpour, Andrea Pellagatti, Anquan Liu, Mohsen Karimi, Luca Malcovati, et al.. Gene expression profiling of erythroblasts from refractory anaemia with ring sideroblasts (RARS) and effects of G-CSF. British Journal of Haematology, 2010, 149 (6), pp.844. ⟨10.1111/j.1365-2141.2010.08174.x⟩. ⟨hal-00552589⟩