# Eltombopag: Novel Mode of Action on Normal and Aplastic Anemia Hematopoietic Stem Cells

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $658,812

## Abstract

Summary
Idiopathic aplastic anemia (AA) is characterized by immune-mediated hematopoietic stem and
progenitor cells (HSPCs) destruction resulting in deficiencies across all hematopoietic lineages
and bone marrow failure. Despite of the therapeutic successes of immunosuppressive therapies
(IST), approximately one third of patients remain refractory and many of the responses are
incomplete. Recently, a synthetic thrombopoietin receptor (TPOR) agonist, Epag has been shown
to be effective in AA. In addition to the anticipated effect on platelet counts, Epag also produced
remarkable tri-lineage hematopoiesis. These effects expanded the indication spectrum of Epag
from immune thrombocytopenic purpura to AA, establishing this drug as an essential hematologic
therapeutic. Recent studies demonstrate that Epag’s hematopoietic activity is also observed in
murine models despite the lack of binding to murine TpoR. We confirmed similar effects in murine
cells where Epag treatment remarkably expanded HSCs without any effect on the TpoR signaling.
These observations suggested that a significant part of Epag’s activities are TPOR independent,
in contrast to peptide TPO analogs, e.g., romiplostin. These TPOR independent effects of Epag
were hypothesized to be due to its iron chelating properties, but the molecular mechanism as to
how this iron-binding could drive the HSPCs expansion remains speculative. Epag effects on
intracellular iron may affect certain iron-dependent epigenetic pathway/s that promote
HSPCs self-replication. For instance, TET-dioxygenases (TET1-3) are Fe2+- and α-
ketoglutarate (αKG) dependent DNA-dioxygenases, which mediate CpG demethylation
of promoters and enhancers in HSPCs. Consequently, by changing gene expression
patterns, TETs control HSPCs expansion and differentiation. TET2 is the most abundant
TET-dioxygenase in HSPCs, and somatic loss-of-function (LOF) mutations of this gene
frequently occur in myeloid neoplasia and clonal hematopoiesis of indeterminate potential
(CHIP), a prodromal condition in otherwise healthy elderly individuals characterized by
high progression rate to a frank leukemia. Our proposal is designed to determine the
effects of Epag on normal hematopoiesis mediated by its ability to inhibit TET-activity.
Based on our analysis of clinical data coupled with biochemical analysis we hypothesize that,
Epag-mediated TET- inhibition is responsible for tri-lineage response in AA via HSC expansion
and on the biochemical level decreased 5hmC content leading to hypermethylation as a result of
direct inhibition of TET2. Our current proposal will provide a proof of concept for the reversible
transient TET-inhibition as a basis for HSC expansion that may restore normal hematopoiesis.

## Key facts

- **NIH application ID:** 10519745
- **Project number:** 1R01DK131923-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Babal K Jha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $658,812
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519745

## Citation

> US National Institutes of Health, RePORTER application 10519745, Eltombopag: Novel Mode of Action on Normal and Aplastic Anemia Hematopoietic Stem Cells (1R01DK131923-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10519745. Licensed CC0.

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