Iron Removal Cures Anemia
ironjustice
Consequent Iron Chelation Therapy in Patients with
Low Risk Myelodysplastic Syndrome Leads to up-Regulation of .CXCL12,
JAK2 and HSF2: Possible Link Between Iron Chelation and
Improvement of Erythropoiesis.
Florian Nolte*,1, Martin Neumann*,2, Ouidad Benlasfer*,3,
Sandra Heesch, MS*,4, Eckhard Thiel5, Uwe Platzbecker6
and Wolf-Karsten Hofmann*,7
1 Hematology, Oncology, Charite, CBF, Berlin, Germany,
2 Medizinische Klinik III (Haematologie, Onkologie und
Transfusionsmedizin),
Charite Campus Benjamin Franklin (Charite Centrum 14), Berlin,
Germany,
3 Department of Hematology and Oncology, Charite Campus Benjamin
Franklin,
Berlin, Germany,
4 Hematology, Oncology, Charite, Campus Benjamin Franklin, Berlin,
Germany,
5 Department of Hematology and Oncology, Charitè Campus Benjamin
Franklin,
Berlin, Germany,
6 University Hospital Dresden, Dresden, Germany,
7 Department of Hematology and Oncology, University Hospital
Mannheim,
Mannheim, Germany
Abstract 2787
Poster Board II-763
Myelodysplastic syndromes (MDS) are characterized by ineffective
hematopoiesis and an increased risk of evolution to acute myeloid
leukemia.
The majority of MDS patients will depend on regular transfusions
of packed red blood cells (PRBC) during their course of disease
due to symptomatic anemia.
Since recurrent transfusions of PRBC will result in iron overload
with the risk of damage of organs such as heart, endocrine glands
and the liver, consequent iron chelation therapy (IC) became an
important element of supportive care in MDS patients.
Recently, the availability of the oral iron chelator deferasirox
provides a convenient management of iron overload in MDS.
Since intensive IC has been shown to improve hematopoiesis in iron
overloaded patients we performed gene expression profiling on
patients with low or intermediate MDS prior and after IC, to
elucidate wheter IC leads to alteration of genes involved in
hematopiesis, in particular in erythropoiesis.
Heparinized bone marrow samples were obtained after informed
consent from 6 MDS patients (2 refractory anemia, 4 refractory
anemia with ringed sideroblasts) upon initial diagnosis of iron
overload (prior IC) and after a period of 1 year of iron chelation
(after IC) with the oral iron chelator deferasirox.
CD34+ hematopoietic progenitor as well as CD71+ erythroid progenitor
cells were isolated by high gradient magnetic cell separation
(Miltenyi Biotech, Bergisch Gladbach, Germany).
RNA was extracted from CD34+ cells and CD71+ cells using TRIzol
reagent (Invitrogen, Life Technologies, Grand Island, NY) according
to the manufacturer's protocol.
Quality controlled RNA was hybridized according to the standard
Affymetrix protocol to HG-U133 Plus 2.0 microarrays.
Data analysis was performed using the Gene Spring Software version
4.0 (Silicon genetics, San Carlos, CA). Restrictions were set as
follows: only genes that were ‘present' in at least 75% of samples
were used for further analyses, genes were considered as
‘differentially expressed' when they showed at least 3 fold change
between the different groups.
Statistical significance was calculated by non-parametric t-test,
with P < 0.05.
In a first step we compared gene expression patterns of CD71+ cells
in MDS patients prior and after IC.
In total 106 probe sets representing unique genes, hypthetical
proteins and open reading frames matched the restriction settings.
In an intensive survey on these genes we identified several genes
that have been associated with erythropoiesis including Stromal
derived factor-1 (CXCL12), Janus kinase 2 (JAK2), and Heat shock
transcription factor 2 (HSF2).
To exclude that these changes in gene expression where due to the
natural course of the disease in specific patients, we compared
gene expression of CD71+ cells from patients after IC to an
independent test set of CD71+ MDS samples (n=12).
Interestingly, we still found an aberrant expression of these genes,
indicating that the observed gene expression changes were related to
the IC in these patients rather than to the natural course of
diesease.
However, we were not able to find an altered expression of these
genes
in CD34+ progenitor cells prior and after IC, suggesting that the
effect on gene expression is restricted to CD71+ cells.
Iron overload is an inevitable side effect of regular blood
transfusions
in MDS patients.
Intensive IC has been shown to improve erythropoiesis in iron
overloaded
patients.
We found, that IC results in upregulation of Stromal derived
factor-1,
Janus kinase 2 and Heat shock transcription factor 2 all of them
known
to regulate hematopoiesis.
Moreover, HSF2 and JAK2 have been closely involved in regulation of
erythropoiesis.
JAK2 deficiency has been shown to result in abrogated erythropoiesis
and therefore increase of JAK2 expression after iron chelation might
link IC to improvement of erythropoiesis and subsequently decrease
of transfusion requirement in some patients receiving IC.
Disclosures: Hofmann: Novartis Oncology, Nürnberg, Germany: Research
Funding.
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