TY - JOUR
T1 - Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice
AU - Hofmann, Inga
AU - Geer, Mitchell J.
AU - Vogtle, Timo
AU - Crispin, Andrew
AU - Campagna, Dean R.
AU - Barr, Alastair
AU - Calicchio, Monica L.
AU - Heising, Silke
AU - van Geffen, Johanna P.
AU - Kuijpers, Marijke J. E.
AU - Heemskerk, Johan W. M.
AU - Eble, Johannes A.
AU - Schmitz-Abe, Klaus
AU - Obeng, Esther A.
AU - Douglas, Michael
AU - Freson, Kathleen
AU - Pondarre, Corinne
AU - Favier, Remi
AU - Jarvis, Gavin E.
AU - Markianos, Kyriacos
AU - Turro, Ernest
AU - Ouwehand, Willem H.
AU - Mazharian, Alexandra
AU - Fleming, Mark D.
AU - Senis, Yotis A.
PY - 2018/9/27
Y1 - 2018/9/27
N2 - 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 germ line 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.
AB - 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 germ line 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.
KW - GRAY PLATELET SYNDROME
KW - BONE-MARROW FIBROSIS
KW - D DEFICIENCY RICKETS
KW - IDIOPATHIC MYELOFIBROSIS
KW - MYELOPROLIFERATIVE NEOPLASMS
KW - MYELOID METAPLASIA
KW - CHILDHOOD
KW - CHILDREN
KW - PROTEIN
KW - GENE
U2 - 10.1182/blood-2017-08-802769
DO - 10.1182/blood-2017-08-802769
M3 - Article
C2 - 29898956
SN - 0006-4971
VL - 132
SP - 1399
EP - 1412
JO - Blood
JF - Blood
IS - 13
ER -