Abstract
Eltrombopag, an FDA-approved non-peptidyl thrombopoietin receptor agonist, is clinically used for the treatment of aplastic anemia, a disease characterized by hematopoietic stem cell failure and pancytopenia, to improve platelet counts and stem cell function. Eltrombopag treatment results in a durable trilineage hematopoietic expansion in patients. Some of the eltrombopag hematopoietic activity has been attributed to its off-target effects, including iron chelation properties. However, the mechanism of action for its full spectrum of clinical effects is still poorly understood. Here, we report that eltrombopag bound to the TET2 catalytic domain and inhibited its dioxygenase activity, which was independent of its role as an iron chelator. The DNA demethylating enzyme TET2, essential for hematopoietic stem cell differentiation and lineage commitment, is frequently mutated in myeloid malignancies. Eltrombopag treatment expanded TET2-proficient normal hematopoietic stem and progenitor cells, in part because of its ability to mimic loss of TET2 with simultaneous thrombopoietin receptor activation. On the contrary, TET inhibition in TET2 mutant malignant myeloid cells prevented neoplastic clonal evolution in vitro and in vivo. This mechanism of action may offer a restorative therapeutic index and provide a scientific rationale to treat selected patients with TET2 mutant–associated or TET deficiency–associated myeloid malignancies.
Highlights
Idiopathic aplastic anemia is characterized by immune-mediated hematopoietic progenitor and stem cell (HSPC) destruction, resulting in deficiencies across all hematopoietic lineages [1,2,3]
Subsequent studies confirmed the efficacy of Epag in de novo and refractory aplastic anemia [13] for increasing both the magnitude of response and the number of responders
Clinical and experimental observations suggest that a significant part of the hematopoietic activities of Epag is independent of its ability to activate thrombopoietin receptor (TPOR)-mediated signaling [14]
Summary
Idiopathic aplastic anemia is characterized by immune-mediated hematopoietic progenitor and stem cell (HSPC) destruction, resulting in deficiencies across all hematopoietic lineages [1,2,3]. Primary murine bone marrow mononuclear cells were treated with vehicle, TPO, Epag, or Apag, and we observed that only Epag treatment reduced 5hmC compared with vehicle (Figure 2, F and G).
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