Thrombopoietin: tickling the HSC's fancy

Abstract

Thrombopoietin (THPO) has been well characterized as a key regulator of platelet production. THPO also plays an important role in the maintenance and regulation of hematopoietic stem cells (HSCs). In this issue of EMBO Molecular Medicine, Pecci et al (2018) describe a newly identified homozygous mutation in THPO causing congenital amegakaryocytic thrombocytopenia, a disease characterized by a significant impairment in platelet production with rapid onset of aplastic anemia within a few years. The paper nicely investigates the underlying pathogenic mechanisms of this disease. Importantly, this study, in tandem with other recent ones, shows that this rare genetic form of aplastic anemia is treatable with THPO receptor agonists, emphasizing the paramount role of genetic testing in cases of aplastic anemia and other bone marrow failure disorders. This report also refines our understanding of the role of THPO in human HSC function and illustrates the important biological insight that can be gained through studies of such rare genetic disorders.

Figure 1. Mechanisms of thrombopoietin signaling in HSCs and other progenitors

THPO binds to its receptor, MPL, resulting in homodimerization of MPL. Dimerization of MPL leads to activation of multiple downstream signaling pathways as shown, predominantly through the receptor‐associated tyrosine kinase, JAK2. Activation of these pathways supports the self‐renewal, proliferation, survival, and differentiation of HSCs and also supports megakaryocyte/platelet production. Previously, mutations in MPL have been reported as the predominant cause of CAMT. Recent studies of CAMT cases with THPO mutations have been reported here and elsewhere. These cases are distinct from other causes of CAMT in that they can be treated with MPL agonists.