The hematopoietic action of the thrombopoietin receptor (TPO-R) agonist eltrombopag () occurs at the stem cell level through its effects on iron chelation that in turn leads to hematopoietic stem cell (HSC) stimulation and self-renewal, investigators report.
Studying the effects of eltrombopag treatment in mouse models and in bone marrow cells isolated from patients,, from the Albert Einstein College of Medicine, New York, and her colleagues found that eltrombopag’s stimulatory effects on stem cell self-renewal were independent of the thrombopoietin receptor.
“The iron chelation–dependent mechanism of [eltrombopag] is very likely to confer clinical relevance in the context of enhancing TPO-R–dependent HSC stimulation and reinforcing stem cell identity through wide-ranging iron-dependent metabolic reprogramming, which increases healthy stem cells without causing their exhaustion in bone marrow failure syndromes, as well as aid in preserving functional HSCs under cellular stress (such as transplantation, cytotoxic treatment, or irradiation),” they wrote in.
To gain insight into the effects of eltrombopag on the earliest stages of hematopoiesis, the investigators conducted a series of experiments, starting with an assessment of the effects of the agent on the functional hallmarks of primary human stem cells.
Using assays for differentiation, self-renewal, and cell proliferation in human bone marrow cell lines, they found that eltrombopag acts directly on multilineage hematopoiesis by fostering commitment to differentiation at the multipotent progenitor (MPP) cell level and by enhancing self-renewal of hematopoietic stem cells.
Next, they investigated whether eltrombopag promoted hematopoiesis by activating the TPO-R, or through a different mechanism, and found that its action was independent of the thrombopoietin receptor. Specifically, they found that eltrombopag “elicits gene expression alterations in HSCs consistent with a molecular response to reduced intracellular iron content, consisting of decreased glycolysis and enhanced lipid and protein catabolic pathway activation.”
To show that the effect was independent of TPO-R, they then turned to mouse models (eltrombopag is known to activate TPO-R signaling in primate cells, including in humans, but cannot do so in mice, they explained). They showed that in mice, eltrombopag is capable of stimulating HSCs even in the absence of action on the TPO-R.
They also demonstrated that HSCs from both humans and mice have evidence of changes in metabolism and in gene expression that were consistent with reduction of labile iron pools that stem cells rely on for maintenance. When they preloaded cells with iron, the stimulatory effects of eltrombopag were negated, further supporting the iron-chelating effects of the drug on HSC stimulation.
Finally, they looked at HSC function in bone marrow mononuclear cells from patients with immune thrombocytopenia who were being treated with eltrombopag and found a threefold greater increase in the number of functional HSCs, compared with samples from patients treated with the TPO-R agonist romiplostim (), which does not have iron-chelating properties.
“Together, our data demonstrate a TPO-R–independent stem cell stimulatory function of EP and suggest that free intracellular iron pools may serve as a rheostat for HSC maintenance,” the investigators wrote.
The study was supported by the New York State Department of Health. Dr. Will and two coauthors reported research support from GlaxoSmithKline and Novartis, and serving as consultants for Novartis. Two of the co-authors are employees of Novartis.
SOURCE: Kao YR et al. Sci Transl Med. 2018 Sep 12;10(458).