Hereditary thrombocythemia caused by a thrombopoietin (THPO) gain-of-function mutation associated with multiple myeloma and congenital limb defects

Abstract

Hereditary thrombocythemia (HT) has been described as a rare benign disorder caused by mutations in the thrombopoietin (THPO) or the c-Mpl receptor genes. Here we report two families with HT resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects, whereas in the other one member developed early-onset multiple myeloma. These observations, together with previously reported patients, suggest that THPO gain of function may dysregulate the hemangioblast and disturb vasculogenesis and hematopoietic development. Overstimulation of the THPO pathway might therefore predispose to clonal hematopoietic disease and to congenital abnormalities.

The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis

“…25 Overstimulation of the THPO pathway through either c-Mpl or THPO gain-of-function mutations are thought to contribute to chronic myeloproliferative disorders in patients who are negative for the JAK2 V617F and the CALR mutations. [19][20][21][49][50][51][52][53][54][55][56] The P106L mutation causing familiar HT may have a similar oncogenic potential, although myeloproliferative disorders have not (yet) developed in the families described here or previously. 9 In conclusion, our study uncovers that correct glycosylation, subcellular transport, distribution, and cell surface localization are not required for active c-Mpl downstream signaling, but that cell surface localization is required for controlling THPO levels and platelet homeostasis.…”

“…[19][20][21][49][50][51][52][53][54][55][56] The P106L mutation causing familiar HT may have a similar oncogenic potential, although myeloproliferative disorders have not (yet) developed in the families described here or previously.…”

Thrombocythemia 1 With THPO Variant (c.13+1G>A) Diagnosed Using Targeted Exome Sequencing: First Case in Korea

“…Several studies c.13+1G > C Likely pathogenic thrombocythemia Increased Hematologic malignancy: early-onset multiple myeloma at 39 years of age *The variants were classified according to the 2015 ACMG/AMP guidelines based on the descriptions in each study. **These two families were described together in the same report [8]. Abbreviation: THPO, thrombopoietin.…”

“…Dear Editor, Hereditary thrombocythemia is a very rare autosomal dominant disorder associated with polyclonal hematopoiesis of the megakaryocytic lineage [1,2]. Thrombocythemia 1 (THCYT1), caused by THPO variant, has been reported in Dutch [3,4], Japanese [5,6], Polish [7], Italian [1], Filipino [2], and German [8] families. Here, we report the first case of a Korean boy diagnosed as having THCYT1 using next-generation sequencing ( Table 1).…”

“…The multiple upstream AUG codons of the 5´-untranslated region (UTR) in THPO interrupt translation and prevent overproduction of this cytokine [7]. Variants at position +1 of the THPO intron 3 splice donor site result in the skipping of exon 3 and loss of the inhibitory 5´-UTR sequence, thereby disrupting the translational regulation and resulting in increased THPO production and thrombocythemia [4,7,8]. A possible mechanism for the early leukocytosis in patients with thrombocythemia can be related to the additional role of THPO in regulating hematopoietic stem cell viability [9,10].…”