Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim

Abstract

Congenital amegakaryocytic thrombocytopenia (CAMT) is an inherited disorder characterized at birth by thrombocytopenia with reduced megakaryocytes, which evolves into generalized bone marrow aplasia during childhood. Although CAMT is genetically heterogeneous, mutations of MPL, the gene encoding for the receptor of thrombopoietin (THPO), are the only known disease‐causing alterations. We identified a family with three children affected with CAMT caused by a homozygous mutation (p.R119C) of the THPO gene. Functional studies showed that p.R119C affects not only ability of the cytokine to stimulate MPL but also its release, which is consistent with the relatively low serum THPO levels measured in patients. In all the three affected children, treatment with the THPO‐mimetic romiplostim induced trilineage hematological responses, remission of bleeding and infections, and transfusion independence, which were maintained after up to 6.5 years of observation. Recognizing patients with THPO mutations among those with juvenile bone marrow failure is essential to provide them with appropriate substitutive therapy and prevent the use of invasive and unnecessary treatments, such as hematopoietic stem cell transplantation or immunosuppression.

Thrombopoietin: tickling the HSC's fancy

“…The cases described in this paper and in the previous studies all have reduced serum levels of THPO, whereas ordinarily THPO levels should be elevated in cases of aplastic anemia or other forms of thrombocytopenia (Dasouki et al, 2013;Pecci et al, 2018;Seo et al, 2017). This finding contrasts with a recent report of mutations in the cytokine erythropoietin that allow for effective synthesis and where serum levels were elevated in the patients, but downstream signaling was impaired as a result of altered binding properties by the mutated ligand (Kim et al, 2017).…”

“…However, three recent papers have now identified a new mechanism by which CAMT can arise, and a distinct treatment approach for these cases. Homozygous mutations in THPO can result in CAMT that evolves rapidly to aplastic anemia (Dasouki et al , ; Pecci et al , ; Seo et al , ). In this issue, Pecci et al () identify a homozygous mutation in THPO (chr3:184091244 C>T in hg19 that results in a missense change of p.R119C) in a family where multiple children have CAMT.…”

“…Homozygous mutations in THPO can result in CAMT that evolves rapidly to aplastic anemia (Dasouki et al , ; Pecci et al , ; Seo et al , ). In this issue, Pecci et al () identify a homozygous mutation in THPO (chr3:184091244 C>T in hg19 that results in a missense change of p.R119C) in a family where multiple children have CAMT. The mechanistic follow‐up studies performed have helped to extend our understanding of how CAMT can arise in these cases.…”

“…Importantly, this new insight will not only provide a paradigm for understanding how this pathway can be perturbed in rare conditions, such as CAMT, but will also provide insights into approaches to modulate this signaling pathway for treating more common conditions, such as idiopathic aplastic anemia, where MPL agonists are already showing efficacy (Townsley et al, 2017). The work from Pecci et al (2018) in this issue and the other recent related articles provide the first steps in this direction and more generally demonstrate how naturally occurring variations can enable us to gain important insights into human biology. THPO binds to its receptor, MPL, resulting in homodimerization of MPL.…”

Thrombopoietin receptor agonists in hereditary thrombocytopenias

“…Moreover, three of these patients were in the phase of generalized bone marrow aplasia, and all of them obtained a trilineage hematological response. It is of note that two patients were still responsive to romiplostim after > 6 years of treatment [38,39].…”