Identification of MPL R102P Mutation in Hereditary Thrombocytosis

Abstract

The molecular basis of hereditary thrombocytosis is germline mutations affecting the thrombopoietin (TPO)/TPO receptor (MPL)/JAK2 signaling axis. Here, we report one family presenting two cases with a mild thrombocytosis. By sequencing JAK2 and MPL coding exons, we identified a germline MPL R102P heterozygous mutation in the proband and his daughter. Concomitantly, we detected high TPO levels in the serum of these two patients. The mutation was not found in three other unaffected cases from the family except in another proband's daughter who did not present thrombocytosis but had a high TPO level. The MPL R102P mutation was first described in congenital amegakaryocytic thrombocytopenia in a homozygous state with a loss-of-function activity. It was previously shown that MPL R102P was blocked in the endoplasmic reticulum without being able to translocate to the plasma membrane. Thus, this case report identifies for the first time that MPL R102P mutation can differently impact megakaryopoiesis: thrombocytosis or thrombocytopenia depending on the presence of the heterozygous or homozygous state, respectively. The paradoxical effect associated with heterozygous MPL R102P may be due to subnormal cell-surface expression of wild-type MPL in platelets inducing a defective TPO clearance. As a consequence, increased TPO levels may activate megakaryocyte progenitors that express a lower, but still sufficient level of MPL for the induction of proliferation.

Keywords: CAMT; JAK2; MPL R102P; thrombocytopenia; thrombocytosis; thrombopoietin.

Figure 1

Heterozygous MPL R102P mutation induces a mild thrombocytosis with high thrombopoietin (TPO) levels. Pedigree from a family harboring a mild thrombocytosis with platelet counts around 600 × 10⁹/L. The proband indicated by an arrow was diagnosed at 42 years old and one of her daughter was 21 years old. MPL was sequenced and a heterozygous MPL R102P mutation was identified. TPO levels were found elevated 119 and 260 pg/mL. Another daughter presented a high TPO level 131 pg/mL but without disease.

Figure 2

Model of MPL R102P function. In wild-type, MPL is increasingly upregulated in megakaryocytic progenitors (MK progenitors) and platelets. The level of thrombopoietin (TPO) is controlled by the platelet mass due to the internalization and degradation of TPO/MPL/JAK2 complexes. In homozygous MPL R102P situation, MPL cannot signal to induce megakaryopoiesis and platelets production even if the TPO level is high since it is blocked in the endoplasmic reticulum (ER). In MPL R102P heterozygous condition, only wild-type MPL is expressed at the cell surface leading to subnormal expression in platelets and defective TPO clearance. Therefore, the TPO levels increased and TPO is able to favor the proliferation of MK progenitors through the wild-type MPL, leading to a thrombocytosis.