Invernizzi_EU Haematology 03/03/2010 16:46 Page 37
Iron Overload, Oxidative Damage and Ineffective Erythropoiesis in Myelodysplastic Syndromes
result in damage to vital organs there is a rationale for iron chelation Figure 4: Possible Pathogenetic Mechanism
therapy. Oxidative stress mediated by iron overload may induce
apoptosis in haematopoietic progenitors.
44
Interestingly, increased Mitochondrion
serum non-transferrin-bound iron levels were observed in MDS,
10
and a
correlation was found between serum ferritin levels of low-risk MDS
patients and ROS in their erythrocytes and platelets.
14
Oxidative
damage
The contribution of iron overload to ineffective haematopoiesis is
Fe/S cluster
synthesis
evident also by the reduction in transfusion requirement and the
increase in platelet and neutrophil counts following iron chelation
Fe
2+
Fe
therapy.
37
Iron chelation therapy was also able to reduce toxic free
iron species and parameters of oxidative stress as well as ROS-
mediated hypoxic suppression of hepcidin in low-risk iron-overloaded
Heme synthesis
patients with MDS.
45,46
FtMt
Iron Overload and Mitochondrial Dysfunction in
Refractory Anaemia with Ring Sideroblasts
As regards RARS pathogenesis, several studies highlight the In refractory anemia with ring sideroblasts (RARS), the aberrant expression of mitochondrial
association between impaired iron homeostasis and mitochondrial
ferritin (FtMt) may reflect a defence mechanism of the cell against the oxidative damage
caused by excess iron. In the absence of iron utilisation for heme synthesis, further excessive
dysfunction. It is well known that mitochondrial DNA lesions in genes iron accumulation may cause FtMt degradation, damage mitochondria and trigger apoptosis.
encoding enzymes of the electron transport chain are involved in both
acquired and inherited sideroblastic anaemia and pathways, including mitochondria to the cytoplasm.
52
All these findings suggest that
mitochondrial oxidative phosphorylation. Thiamine metabolism and mitochondrial dysfunction, in particular excessive ROS production and
iron–sulphur biosynthesis have been identified as primary defects in excess iron accumulation, plays a critical role in the physiopathological
the hereditary forms.
47
These defects result in pathological iron mechanism of anaemia in RARS.
53
Experimental data support this
deposition within mitochondria. suggestion. In a crimsonless (crs) zebrafish mutant, the mutation of a
mitochondrial heat shock protein (HSPA9B) produces oxidative stress
Interestingly, in RARS it was observed that the iron deposited in the and apoptosis in blood cells.
54
Superoxide dismutase (SOD2) deficiency
perinuclear mitochondria of ringed sideroblasts is present in the form induces the phenotype of sideroblastic anaemia in chimaeric mice, as
of FtMt
48
(see Figure 3). Initial data suggested that the expression of the mitochondrial enzyme SOD2 is the principal defence against the
FtMt in these cells was a response to mitochondrial iron accumulation. toxicity of superoxide anion radicals.
55
However, the finding that bone marrow cells from patients with RARS
start to express FtMt in the early stages of erythroid differentiation, Future Directions
before evident iron accumulation,
49
indicated a more complex Over the past decade substantial progress has been made in the
mechanism of gene regulation. elucidation of the mechanisms by which mitochondria protect
themselves from iron excess and associated oxidative damage.
FtMt overexpression in RARS erythroid progenitors was paralleled by However, further studies are needed to fully clarify the possible
an upregulation of genes involved in the process of erythroid pathogenetic role of iron-induced oxidative damage in the
differentiation and was associated with cytochrome C release, with ineffective erythropoiesis of MDS. Further studies should also
subsequent initiation of the intrinsic apoptotic pathway and increased identify the signalling pathways implicated in the loss of
sensitivity to death ligands triggering the extrinsic pathway.
49
Even if haematopoietic progenitors due to ROS generation and oxidative
further studies are needed to clarify whether FtMt overexpression is stress. The results of these studies might also be important from a
the cause or the result of mitochondrial iron deposition and whether clinical point of view, as they might provide the rationale for
FtMt is expressed in all conditions of mitochondrial iron excess, therapeutic strategies based on the combination of iron chelators
findings suggest that, initially in RARS, the iron accumulation in FtMt and antioxidants for MDS patients. A prolonged high-dose use of
may be protective. It may preserve mitochondrial DNA integrity and these agents may inhibit apoptosis and promote cell differentiation
increase cell resistance to oxidative damage. In the absence of iron by reducing abnormal cytosolic or mitochondrial iron accumulation
utilisation for heme synthesis, FtMt may potentially degrade to a and, consequently, oxidative damage. n
haemosiderin-like molecule that is redox-active, leading to
subsequent mitochondrial damage, impairing heme synthesis and
altering the balance between cell growth and death (see
Rosangela Invernizzi is an Associate Professor of Internal
Figure 4). The
Medicine and Chief of the Haematological Cytology
recent finding that FtMt overexpression in a neoplastic cell line
Laboratory at the University of Pavia. She is a member of
sensitises cells to oxidative stress via an iron-mediated mechanism
the Italian Societies of Haematology, Experimental
and increases apoptosis levels supports this suggestion.
50
Haematology, Histochemistry and Internal Medicine, and
the European Haematology Association. Dr Invernizzi’s
main field of interest is myelodysplastic syndromes. She
Other recent studies have demonstrated that CD34
+
cells from patients
recently investigated the role of bone marrow cell
with RARS have a peculiar gene expression profile characterised by
apoptosis in the molecular pathogenesis of these
disorders and the role of a novel mitochondrial ferritin in regulating mitochondrial iron
upregulation of mitochondria-related genes, in particular those of heme
homeostasis and heme synthesis. She graduated in medicine and has specialised in
synthesis.
51
On the other hand, some genes are downregulated. An
haematology, internal medicine and oncology at Pavia University.
example of this is ABCB7, which encodes a transporter of iron from the
EUROPEAN HAEMATOLOGY 37
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