| Authors | Hofmann, I., Geer, M.J., Vögtle, T., Crispin, A., Campagna, D.R., Barr, A.J., Calicchio, M.L., Heising, S., van Geffen, J.P., Kuijpers, M.J.E., Heemskerk, J.W.M., Eble, J.A., Schmitz-Abe, K., Obeng, E.A., Douglas, M., Freson, K., Pondarré, C., Favier, R., Jarvis, G.E., Markianos, K., Turro, E., Ouwehand, W.H., Mazharian, A., Fleming, M.D. and Senis, Y. |
|---|
| Abstract | Unlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germline loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25 or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor. |
|---|
| Keywords | myelofibrosis, congenital myelofibrosis, familial myelofibrosis, myeloproliferative neoplasm, C6orf25, MPIG6B, G6b-B, megakaryocytes, platelets, thrombocytopenia, transgenic mouse |
|---|