Page 649 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 40 Thalassemia Syndromes 551

activation of the Janus kinase 2 (JAK2)–STAT5 (signal transducers Hepcidin
and activators of transcription 5) pathway promotes unnecessary
disproportionate proliferation of erythroid progenitors, but other The role of hepcidin in iron regulation is reviewed elsewhere (Chap-
factors suppress serum hepcidin levels leading to dysregulation of iron ters 35 and 36).
metabolism. Preclinical studies suggest that JAK2 inhibitors, hepci- Several studies demonstrate that erythropoietic iron demand
din agonists, and exogenous transferrin may help to restore normal influences hepcidin expression to a greater degree than anemia or
erythropoiesis and iron metabolism and reduce splenomegaly. 43–53 nonhematopoietic iron stores. 38,39 In particular, studies in β-thalassemia
demonstrate that hepcidin expression is disproportionally low relative
to the degree of iron overload. 40–42 These and previous studies pro-
JAK2 posed that an “erythroid factor” suppresses hepcidin synthesis. Part
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of this regulation is related to erythroferrone, a hormone produced
In murine models and patients with β-thalassemia, erythroid precur- by erythroblasts in response to EPO and suppresses hepcidin. Mice
sors express elevated levels of the phosphorylated active form of JAK2 that are deficient in erythroferrone fail to suppress hepcidin produc-
(pJAK2) and other downstream signaling molecules that promote tion during erythropoietic stress like experimental hemorrhage.
proliferation and inhibit differentiation of erythroid progenitor Furthermore, thalassemia intermedia mice (Hbbth3/+) have high
cells. 54,55 A recent study showed that JAK2 activation upregulated levels of erythroferrone expression that contributes to hepcidin
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the transcription factor ID1 ; high levels of ID1 have been found suppression. 64
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to inhibit cellular differentiation. JAK2 signaling also activates the Other factors are also important in hepcidin regulation. Twisted
phosphoinositol-3-kinase (PI3K)–AKT pathway, which plays an gastrulation-1 (TWSG1) has been isolated from immature erythroid
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important role in regulating cell survival and the activity of the precursors in β-thalassemic mice. As a small secreted cysteine-rich
transcription factor forkhead box O3 (FOXO3), which modulates protein able to influence bone morphogenetic proteins signaling, the
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oxidative stress during erythropoiesis. Taken together, findings from expression of TWSG1 is increased in β-thalassemic mice and represses
these studies suggest a model in which persistent phosphorylation hepcidin in vitro. 65,66 However, whether this factor is present in other
of JAK2 as a consequence of high EPO levels induces erythroid conditions and how efficiently TWSG1 represses hepcidin in physi-
hyperplasia and massive extramedullary hematopoiesis and the early ologic conditions are still unclear. Growth differentiation factor-15
erythroid progenitors that fail to differentiate colonize and proliferate (GDF15) has been isolated from the sera of β-thalassemic patients
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predominantly in the spleen and liver, thus contributing to hepato- and in other individuals exhibiting features of IE, such as myelodys-
splenomegaly. Given the central role of JAK2 in the pathophysiology plastic syndrome (MDS) and congenital dyserythropoietic anemia
of IE, it has been hypothesized that JAK2 inhibitors may be effective type I and II and an inverse correlation with hepcidin levels has been
in modulating some of these compensatory mechanisms that lead to demonstrated. 67–69 GDF15 is a member of the transforming growth
the severe clinical complications associated with β-thalassemia. factor (TGFβ) superfamily of proteins, which are known to control
The activation of the EPO–EPO-Receptor–JAK2 pathway is not cell proliferation, differentiation, and apoptosis in numerous cell
likely the only cause of the limited erythroid differentiation observed types. However, it is possible that in conditions such as β-thalassemia,
in β-thalassemia. It is possible that other factors or abnormal physi- multiple “erythroid factors” suppress hepcidin expression. 70,71 The
ologic conditions present in β-thalassemia come into play, interfering mechanisms of action of GDF15 and TWSG1 in repressing hepcidin
with erythroid cell differentiation. Among the possible factors acting expression remain undefined but are likely to alter the function of
together with JAK2, iron overload, reactive oxygen species (ROS), or proteins that modulate hepcidin production.
the unbalanced synthesis of globin chains or heme can be also con- The TGFβ superfamily of cytokines is important in RBC develop-
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sidered. Iron is essential for all cells but is toxic in excess. It is ment. Activin also plays a role in erythropoiesis and red cell differ-
possible to speculate that thalassemic erythroid cells accumulate an entiation. Recent studies in mice suggest that using an activin receptor
excess of toxic heme associated with free α-chains, leading to the IIA ligand trap (sotatercept) may block activin, decreasing deleterious
formation of ROS, which has been involved with cell RBC hemolysis effects of GDF15, and limiting IE. This class of drugs may also
and altered differentiation. 58,59 improve bone mineral density in thalassemia patients. Clinical trials
Serum iron is bound to transferrin and enters erythroid cells primar- are currently under way. 72
ily via receptor-mediated endocytosis of the transferrin receptor (TfR1). Mice affected by thalassemia intermedia (Hbbth3/+) avoid iron
TfR1 is essential for developing erythrocytes, and reduced TfR1 expres- overload when placed on a low-iron diet or are engineered to over-
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sion is associated with anemia. STAT5-null mice are severely anemic express a moderate level of hepcidin. Reversal of iron overload
and die perinatally. Two studies associated STAT5 to iron homeostasis results in reduced erythroid iron intake, limiting the synthesis of
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showing that ablation of STAT5 leads to a dramatic reduction in the heme and the formation of hemichromes and ROS. Because hemi-
iron regulatory protein 2 and Tfr1 mRNA and protein. 60,61 Both genes chromes and ROS cause IE in β-thalassemia, iron restriction and
were demonstrated to be direct transcriptional targets of STAT5, decreased erythroid iron intake result in more effective erythropoiesis,
establishing a clear link between EPO-R–JAK2–STAT signaling and normalize RBC morphology and lifespan, increase circulating Hb,
iron metabolism. Therefore, it is possible that activation of JAK2 might and reverse splenomegaly. 62,73 Thus, the use of hepcidin agonists or
increase erythroid iron intake and that this might be detrimental in drugs that increase hepcidin expression, decreases iron uptake from
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thalassemic cells, in which part of the iron ends up in toxic hemi- the diet, reduces iron overload, and improves erythropoiesis in TI.
chromes (α-chain/heme aggregates), triggering ROS formation. In TM, repeated blood transfusions are the principal cause of iron
The persistent phosphorylation of JAK2 leads to an increased overload. Despite iron overload, hepcidin concentrations are low;
number of surviving erythroid precursors, contributing to the IE. transfusion also suppresses endogenous erythropoiesis and, as a
Therefore, suppression of JAK2 activity may modulate IE. Based on consequence, results in a transient increase in hepcidin. 40,74,75 Although
this hypothesis, a JAK2 inhibitor was used for 10 days in mice intestinal iron absorption contributes part of the total iron load in
affected by thalassemia intermedia (Hbbth3/+) and demonstrated a these patients, hepcidin therapy may be effective in conjunction with
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reduction in splenomegaly (“nonsurgical splenectomy”). This study transfusion to prevent intestinal iron uptake when endogenous
also demonstrated that JAK2 inhibitors decreased the number of cells hepcidin falls.
expressing cell cycle–related genes and partially reversed the IE,
ameliorating the ratio between erythroid precursors and enucleated
RBCs. 54,62 Thus, although a complete understanding of how JAK2 Transferrin
inhibitors achieve this effect is unavailable, modulation of cell cycle
and differentiation are likely involved. Clinical trials of JAK2 inhibi- TfR1 takes up iron from duodenal enterocytes where iron is absorbed
tors are currently underway in thalassemia major, and will add clarity and from macrophages when iron is recycled from senescent RBCs
to the role of JAK2 in this disease. and delivers it to cells by binding TfR1. Tf saturation is the main