Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin

Abstract

Key Points Germ line biallelic loss-of-function THPO mutations cause BMF. Marrow failure due to THPO mutations is characterized by poor graft function after transplantation but responds to THPO receptor agonists.

Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim

“…However, the prolonged trilineage response to the drug observed in the proband, despite the use of a very low dose and of a non‐conventional administration schedule due to logistic reasons, allows us to hope that the drug will be effective also in this regard. Consistent with our observations, trilineage response to romiplostim was achieved by two affected individuals homozygous for the p.R99W or p.R157* mutations of THPO (Seo et al , ).…”

“…At variance, the serum THPO concentration was not increased in our patients and thus inappropriately lower than expected on the basis of their megakaryocyte–platelet mass. Like p.R119C, also p.R38C led to defective secretion of THPO, a finding that was consistent with the “normal” or low serum levels of THPO found in the other individuals carrying loss‐of‐function mutations of THPO (Dasouki et al , ; Seo et al , ). These observations suggest that measurement of the serum THPO level could be useful to discriminate CAMT patients with THPO mutations from those with MPL variants or other bone marrow failure syndromes.…”

“…Therefore, we cannot exclude that also the Micronesian patients had a clinical course similar to that of CAMT, even if globally less severe, given that marrow aplasia was diagnosed during their adolescence or later. Very recently, Seo and colleagues reported five individuals from three consanguineous families carrying another two homozygous mutations (p.R99W and p.R157*) of THPO (Seo et al , ). Like our patients, these subjects presented with hypo‐megakaryocytic thrombocytopenia without or with anemia or neutropenia, which progressed to trilineage bone marrow aplasia in early childhood.…”

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).…”

“…Importantly, given the identification of these mutations and the characterization performed, the authors in this case were able to ameliorate the pancytopenia present through treatment with the MPL agonist, romiplostim. These results extend the recent successful treatment of two other patients with CAMT due to homozygous THPO mutations with romiplostim and definitively define this condition as a treatable form of aplastic anemia (Seo et al , ). In the future, it will be critical for any patients with aplastic anemia and preceding thrombocytopenia to be screened for THPO mutations, as this condition can be readily reversed with clinically available MPL agonists.…”