Soumit K. Basu, MD, PhD, and Michael Linenberger, MD
Drs. Basu and Linenberger indicated no
relevant conflicts of interest.
Li H, Rybicki AC, Suzuka SM, et al. Transferrin
therapy ameliorates disease in b-thalassemic
mice. Nat Med. 2010;16:177-82.
pathophysiology of β-thalassemia involves both ineffective erythropoiesis and
hemolysis. Reduced or absent β-globin synthesis leads to excess free α-globin
chains, increased apoptosis of erythroid precursors, and markedly shortened
erythrocyte survival due to membrane precipitates of denatured α-globin.
Clinical features, which vary depending on the degree of α:β globin imbalance,
include microcytic anemia, extramedullary hematopoiesis, hepatosplenomegaly,
and iron overload related to dysregulated iron absorption and recycling and
chronic transfusions. In addition to the deleterious effects of parenchymal
cell iron deposition, alterations in iron trafficking and distribution may
contribute to ineffective erythropoiesis through inadequate delivery of
transferrin-bound iron to the massively expanded erythron and generation of
non-transferrin-bound labile plasma iron (LPI), which can mediate free radical
Previous work by Yelena
Ginzburg and colleagues at the New York Blood Center using the Hbbth1/th1 mouse
model of β-thalassemia intermedia demonstrated that iron dextran treatment
significantly improved reticulocyte production, red cell numbers, and
hemoglobin levels by stimulating extramedullary, but not intramedullary,
erythropoiesis.1 Suspecting there was a relative lack of transferrin-bound iron
delivery to the marrow, Li et al. in the Ginzburg laboratory investigated the
effects of human transferrin therapy in Hbbth1/th1 mice. Wild-type (WT) and
β-thalassemic mice were given daily intraperitoneal human apotransferrin or
holotransferrin for 60 days. β-thalassemic mice receiving transferring demonstrated
significant amelioration of anemia, normalization of erythrocyte lifespan,
marked lowering of serum erythropoietin levels, increased proportion of mature
erythroid precursors with fewer apoptotic cells, and decreased
circulating reticulocytes compared to untreated animals. In addition, serum LPI
levels normalized, intraerythrocytic α-globin precipitation decreased,
extramedullary hematopoiesis was suppressed, and spleen size regressed to near
normal. Notably, red cell numbers increased by roughly 50 percent, but mean cell
volume (MCV) and mean cell hemoglobin (MCH) decreased further below the low
baseline values. Hepcidin levels, which are inappropriately low in β-thalassemic
patients and Hbbth1/th1 mice, increased significantly with a corresponding
reduction in hepatic Kupffer cell ferroportin expression. No differences were
noted between mice receiving apotransferrin versus holotransferrin. WT mice
exhibited no transferrin-related toxicities; however, like treated Hbbth1/th1
mice, red cell numbers increased, and MCV and MCH decreased significantly.
responsible for the impressive beneficial effects of transferring injections in
this mouse model were not fully defined. The decreases in MCV and MCH in both
WT and thalassemic mice suggest that excess apotransferrin actually resulted in
less iron per transferrin molecule delivered to individual erythroid
precursors. This would presumably down-modulate heme and globin production2 and
reduce α-globin excess, α-chain precipitates, and cell death. The increase in
hepcidin, which could limit toxicity due to macrophage iron release, might be
modulated by regulatory factors associated with apoptotic erythroid
precursors3,4; however, this too remains speculative. Short-term apotransferrin
administration was safe in one human trial.5 Therefore, pilot studies in
patients with intermediate/severe β-thalassemia are feasible. Recapitulating
these results would be a major advancement if transfusions can be avoided and
complications from extramedullary hematopoiesis and secondary iron overload can
be mitigated. By extension, this principle of “iron redirection” to the
erythron may prove useful in other diseases exhibiting ineffective
erythropoiesis and iron overload.
- Ginzburg YZ, Rybicki
AC, Suzuka SM, et al. Exogenous
iron increases hemoglobin in beta-thalassemic mice. Exp Hematol.
- Chen JJ. Regulation
of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to
anemias. Blood. 2007;109:2693-99.
- Tanno T, Bhanu NV,
Oneal PA, et al. High
levels of GDF15 in thalassemia suppress expression of the iron regulatory
protein hepcidin. Nat Med. 2007;13:1096-1101.
- Tanno T, Porayette P,
Sripichai O, et al. Identification
of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine
and human cells. Blood. 2009;114:181-86.
- Parkkinen J, Sahlstedt
L, von Bonsdorff L, et al. Effect
of repeated apotransferrin administrations on serum iron parameters in patients
undergoing myeloablative conditioning and allogeneic stem cell transplantation.
Br J Haematol. 2006;135:228-34.
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