Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice

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Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice. / Hofmann, Inga; Geer, Mitchell J; Vögtle, Timo; Crispin, Andrew; Campagna, Dean R; Barr, Alastair; Calicchio, Monica L; Heising, Silke; van Geffen, Johanna P; Kuijpers, Marijke J E; Heemskerk, Johan W M; Eble, Johannes A; Schmitz-Abe, Klaus; Obeng, Esther A; Douglas, Michael; Freson, Kathleen; Pondarré, Corinne; Favier, Rémi; Jarvis, Gavin E; Markianos, Kyriacos; Turro, Ernest; Ouwehand, Willem H; Mazharian, Alexandra; Fleming, Mark D; Senis, Yotis A.

In: Blood, 13.06.2018.

Research output: Contribution to journalArticle

Harvard

Hofmann, I, Geer, MJ, Vögtle, T, Crispin, A, Campagna, DR, Barr, A, Calicchio, ML, Heising, S, van Geffen, JP, Kuijpers, MJE, Heemskerk, JWM, Eble, JA, Schmitz-Abe, K, Obeng, EA, Douglas, M, Freson, K, Pondarré, C, Favier, R, Jarvis, GE, Markianos, K, Turro, E, Ouwehand, WH, Mazharian, A, Fleming, MD & Senis, YA 2018, 'Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice', Blood. https://doi.org/10.1182/blood-2017-08-802769

APA

Hofmann, I., Geer, M. J., Vögtle, T., Crispin, A., Campagna, D. R., Barr, A., 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., ... Senis, Y. A. (2018). Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice. Blood. https://doi.org/10.1182/blood-2017-08-802769

Vancouver

Author

Hofmann, Inga ; Geer, Mitchell J ; Vögtle, Timo ; Crispin, Andrew ; Campagna, Dean R ; Barr, Alastair ; Calicchio, Monica L ; Heising, Silke ; van Geffen, Johanna P ; Kuijpers, Marijke J E ; Heemskerk, Johan W M ; Eble, Johannes A ; Schmitz-Abe, Klaus ; Obeng, Esther A ; Douglas, Michael ; Freson, Kathleen ; Pondarré, Corinne ; Favier, Rémi ; Jarvis, Gavin E ; Markianos, Kyriacos ; Turro, Ernest ; Ouwehand, Willem H ; Mazharian, Alexandra ; Fleming, Mark D ; Senis, Yotis A. / Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice. In: Blood. 2018.

Bibtex

@article{253b4f6fce1a4f06bea596bf66b4f4ce,
title = "Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice",
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",
author = "Inga Hofmann and Geer, {Mitchell J} and Timo V{\"o}gtle and Andrew Crispin and Campagna, {Dean R} and Alastair Barr and Calicchio, {Monica L} and Silke Heising and {van Geffen}, {Johanna P} and Kuijpers, {Marijke J E} and Heemskerk, {Johan W M} and Eble, {Johannes A} and Klaus Schmitz-Abe and Obeng, {Esther A} and Michael Douglas and Kathleen Freson and Corinne Pondarr{\'e} and R{\'e}mi Favier and Jarvis, {Gavin E} and Kyriacos Markianos and Ernest Turro and Ouwehand, {Willem H} and Alexandra Mazharian and Fleming, {Mark D} and Senis, {Yotis A}",
note = "Copyright {\textcopyright} 2018 American Society of Hematology.",
year = "2018",
month = jun,
day = "13",
doi = "10.1182/blood-2017-08-802769",
language = "English",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",

}

RIS

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 - Vögtle, 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 - Pondarré, Corinne

AU - Favier, Rémi

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

N1 - Copyright © 2018 American Society of Hematology.

PY - 2018/6/13

Y1 - 2018/6/13

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 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.

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 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.

KW - Myelofibrosis

KW - Congenital myelofibrosis

KW - Familial myelofibrosis

KW - Myeloproliferative neoplasm

KW - C6orf25

KW - MPIG6B

KW - G6b-B

KW - Megakaryocytes

KW - Platelets

KW - Thrombocytopenia

KW - Transgenic mouse

U2 - 10.1182/blood-2017-08-802769

DO - 10.1182/blood-2017-08-802769

M3 - Article

C2 - 29898956

JO - Blood

JF - Blood

SN - 0006-4971

ER -