Skip to main content
Log in

Mouse models of diseases of megakaryocyte and platelet homeostasis

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Platelets are the small anuclear blood cells that are the product of megakaryocytopoiesis, the process of hematopoietic stem cell commitment to megakaryocyte production and the differentiation and maturation of these cells for platelet release. Deregulation or disruption of megakaryocytopoiesis can result in platelet deficiencies, the thrombocytopenias, with attendant risk of hemorrhage or thrombocytosis, a pathological excess of platelet numbers. Mouse models, particularly those engineered to carry genetic alterations modeling mutations associated with human disease, have provided important insights into megakaryocytopoiesis and deregulation of this process in disease. This review focuses on mouse models of diseases of altered megakaryocyte and platelet number, illustrating the profound contribution of these models in validating suspected roles of disease-associated genetic alterations, promoting discovery of new links between genetic mutations and specific diseases, and providing unique tools for better understanding of disease pathophysiology and progression, as well as resources to define drug action or develop new therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abdel-Wahab O (2011) Genetics of the myeloproliferative neoplasms. Curr Opin Hematol 18(2):117–123

    Article  PubMed  Google Scholar 

  • Akada H, Yan D, Zou H, Fiering S, Hutchison RE, Mohi MG (2010) Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood 115:3589–3597

    Article  PubMed  CAS  Google Scholar 

  • Aldrich RA, Steinberg AG, Campbell DC (1954) Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics 13:133–139

    PubMed  CAS  Google Scholar 

  • Alexander WS, Metcalf D, Dunn AR (1995) Point mutations within a dimer interface homology domain of c-Mpl induce constitutive receptor activity and tumorigenicity. EMBO J 14:5569–5578

    PubMed  CAS  Google Scholar 

  • Alexander WS, Roberts AW, Nicola NA, Li R, Metcalf D (1996) Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood 87:2162–2170

    PubMed  CAS  Google Scholar 

  • Al-Qahtani FS (2010) Congenital amegakaryocytic thrombocytopenia: a brief review of the literature. Clin Med Insights Pathol 3:25–30

    Article  PubMed  Google Scholar 

  • Balduini CL, Pecci A, Loffredo G, Izzo P, Noris P, Grosso M, Bergamaschi G, Rosti V, Magrini U, Ceresa IF, Conti V, Poggi V, Savoia A (2004) Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 91:129–140

    PubMed  CAS  Google Scholar 

  • Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061

    PubMed  CAS  Google Scholar 

  • Bergmann AK, Grace RF, Neufeld EJ (2010) Genetic studies in pediatric ITP: outlook, feasibility, and requirements. Ann Hematol 89:S95–S103

    Article  PubMed  Google Scholar 

  • Bernard J, Soulier JP (1948) Not Available. Sem Hop 24:3217–3223

    PubMed  CAS  Google Scholar 

  • Bersenev A, Wu C, Balcerek J, Tong W (2008) Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2. J Clin Invest 118:2832–2844

    PubMed  CAS  Google Scholar 

  • Bersenev A, Wu C, Balcerek J, Jing J, Kundu M, Blobel GA, Chikwava KR, Tong W (2010) Lnk constrains myeloproliferative diseases in mice. J Clin Invest 120:2058–2069

    Article  PubMed  CAS  Google Scholar 

  • Breton-Gorius J, Favier R, Guichard J, Cherif D, Berger R, Debili N, Vainchenker W, Douay L (1995) A new congenital dysmegakaryopoietic thrombocytopenia (Paris-Trousseau) associated with giant platelet alpha-granules and chromosome 11 deletion at 11q23. Blood 85:1805–1814

    PubMed  CAS  Google Scholar 

  • Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adelaide J, Rey J, Vainchenker W, Bernard OA, Chaffanet M, Vey N, Birnbaum D, Mozziconacci MJ (2009) Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23:2183–2186

    Article  PubMed  CAS  Google Scholar 

  • Carmichael CL, Majewski IJ, Alexander WS, Metcalf D, Hilton DJ, Hewitt CA, Scott HS (2009) Hematopoietic defects in the Ts1Cje mouse model of Down syndrome. Blood 113:1929–1937

    Article  PubMed  CAS  Google Scholar 

  • Carpinelli MR, Hilton DJ, Metcalf D, Antonchuk JL, Hyland CD, Mifsud SL, Di Rago L, Hilton AA, Willson TA, Roberts AW, Ramsay RG, Nicola NA, Alexander WS (2004) Suppressor screen in Mpl−/− mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc Natl Acad Sci USA 101:6553–6558

    Article  PubMed  CAS  Google Scholar 

  • Chang AN, Cantor AB, Fujiwara Y, Lodish MB, Droho S, Crispino JD, Orkin SH (2002) GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis. Proc Natl Acad Sci USA 99:9237–9242

    Article  PubMed  CAS  Google Scholar 

  • Chen Z, Shivdasani RA (2009) Regulation of platelet biogenesis: insights from the May-Hegglin anomaly and other MYH9-related disorders. J Thromb Haemost 7(Suppl 1):272–276

    Article  PubMed  CAS  Google Scholar 

  • Chou ST, Opalinska JB, Yao Y, Fernandes MA, Kalota A, Brooks JS, Choi JK, Gewirtz AM, Danet-Desnoyers GA, Nemiroff RL, Weiss MJ (2008) Trisomy 21 enhances human fetal erythro-megakaryocytic development. Blood 112:4503–4506

    Article  PubMed  CAS  Google Scholar 

  • Chow L, Aslam R, Speck ER, Kim M, Cridland N, Webster ML, Chen P, Sahib K, Ni H, Lazarus AH, Garvey MB, Freedman J, Semple JW (2010) A murine model of severe immune thrombocytopenia is induced by antibody- and CD8 + T cell-mediated responses that are differentially sensitive to therapy. Blood 115:1247–1253

    Article  PubMed  CAS  Google Scholar 

  • Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, Bult CJ, Agarwala R, Cherry JL, DiCuccio M, Hlavina W, Kapustin Y, Meric P, Maglott D, Birtle Z, Marques AC, Graves T, Zhou S, Teague B, Potamousis K, Churas C, Place M, Herschleb J, Runnheim R, Forrest D, Amos-Landgraf J, Schwartz DC, Cheng Z, Lindblad-Toh K, Eichler EE, Ponting CP (2009) Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol 7:e1000112

    Article  PubMed  CAS  Google Scholar 

  • Ciovacco WA, Raskind WH, Kacena MA (2008) Human phenotypes associated with GATA-1 mutations. Gene 427:1–6

    Article  PubMed  CAS  Google Scholar 

  • Cocault L, Bouscary D, Le Bousse Kerdiles C, Clay D, Picard F, Gisselbrecht S, Souyri M (1996) Ectopic expression of murine TPO receptor (c-mpl) in mice is pathogenic and induces erythroblastic proliferation. Blood 88:1656–1665

    PubMed  CAS  Google Scholar 

  • Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS (2004) Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice. J Biol Chem 279:41263–41266

    Article  PubMed  CAS  Google Scholar 

  • Dastugue N, Lafage-Pochitaloff M, Pages MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Leonard C, Bilhou-Nabera C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Perot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R (2002) Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Blood 100:618–626

    Article  PubMed  CAS  Google Scholar 

  • Descot A, Rex-Haffner M, Courtois G, Bluteau D, Menssen A, Mercher T, Bernard OA, Treisman R, Posern G (2008) OTT-MAL is a deregulated activator of serum response factor-dependent gene expression. Mol Cell Biol 28:6171–6181

    Article  PubMed  CAS  Google Scholar 

  • Ding J, Komatsu H, Wakita A, Kato-Uranishi M, Ito M, Satoh A, Tsuboi K, Nitta M, Miyazaki H, Iida S, Ueda R (2004) Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 103:4198–4200

    Article  PubMed  CAS  Google Scholar 

  • Ding J, Komatsu H, Iida S, Yano H, Kusumoto S, Inagaki A, Mori F, Ri M, Ito A, Wakita A, Ishida T, Nitta M, Ueda R (2009) The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity. Blood 114:3325–3328

    Article  PubMed  CAS  Google Scholar 

  • Eckly A, Strassel C, Freund M, Cazenave JP, Lanza F, Gachet C, Leon C (2009) Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation. Blood 113:3182–3189

    Article  PubMed  CAS  Google Scholar 

  • El-Harith el-HA, Roesl C, Ballmaier M, Germeshausen M, Frye-Boukhriss H, von Neuhoff N, Becker C, Nurnberg G, Nurnberg P, Ahmed MA, Hubener J, Schmidtke J, Welte K, Stuhrmann M (2009) Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene. Br J Haematol 144:185-194

    Google Scholar 

  • Fielder PJ, Gurney AL, Stefanich E, Marian M, Moore MW, Carver-Moore K, de Sauvage FJ (1996) Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood 87:2154–2161

    PubMed  CAS  Google Scholar 

  • Fisher CL, Pineault N, Brookes C, Helgason CD, Ohta H, Bodner C, Hess JL, Humphries RK, Brock HW (2010) Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood 115:38–46

    Article  PubMed  CAS  Google Scholar 

  • Fishley B, Alexander WS (2004) Thrombopoietin signalling in physiology and disease. Growth Factors 22:151–155

    Article  PubMed  CAS  Google Scholar 

  • Frey BM, Rafii S, Teterson M, Eaton D, Crystal RG, Moore MA (1998) Adenovector-mediated expression of human thrombopoietin cDNA in immune-compromised mice: insights into the pathophysiology of osteomyelofibrosis. J Immunol 160:691–699

    PubMed  CAS  Google Scholar 

  • Fujiwara Y, Browne CP, Cunniff K, Goff SC, Orkin SH (1996) Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc Natl Acad Sci USA 93:12355–12358

    Article  PubMed  CAS  Google Scholar 

  • Geddis AE (2010) Megakaryopoiesis. Semin Hematol 47:212–219

    Article  PubMed  CAS  Google Scholar 

  • Ghilardi N, Skoda RC (1999) A single-base deletion in the thrombopoietin (TPO) gene causes familial essential thrombocythemia through a mechanism of more efficient translation of TPO mRNA. Blood 94:1480–1482

    PubMed  CAS  Google Scholar 

  • Ghilardi N, Wiestner A, Kikuchi M, Ohsaka A, Skoda RC (1999) Hereditary thrombocythaemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene. Br J Haematol 107:310–316

    Article  PubMed  CAS  Google Scholar 

  • Gonin P, Pirzadeh B, Gagnon CA, Dea S (1999) Seroneutralization of porcine reproductive and respiratory syndrome virus correlates with antibody response to the GP5 major envelope glycoprotein. J Vet Diagn Invest 11:20–26

    Article  PubMed  CAS  Google Scholar 

  • Grottum KA, Hovig T, Holmsen H, Abrahamsen AF, Jeremic M, Seip M (1969) Wiskott-Aldrich syndrome: qualitative platelet defects and short platelet survival. Br J Haematol 17:373–388

    Article  PubMed  CAS  Google Scholar 

  • Growney JD, Shigematsu H, Li Z, Lee BH, Adelsperger J, Rowan R, Curley DP, Kutok JL, Akashi K, Williams IR, Speck NA, Gilliland DG (2005) Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106:494–504

    Article  PubMed  CAS  Google Scholar 

  • Gurney AL, Carver-Moore K, de Sauvage FJ, Moore MW (1994) Thrombocytopenia in c-mpl-deficient mice. Science 265:1445–1447

    Article  PubMed  CAS  Google Scholar 

  • Haddad E, Cramer E, Riviere C, Rameau P, Louache F, Guichard J, Nelson DL, Fischer A, Vainchenker W, Debili N (1999) The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation. Blood 94:509–518

    PubMed  CAS  Google Scholar 

  • Hart A, Melet F, Grossfeld P, Chien K, Jones C, Tunnacliffe A, Favier R, Bernstein A (2000) Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity 13:167–177

    Article  PubMed  CAS  Google Scholar 

  • Hokom MM, Lacey D, Kinstler OB, Choi E, Kaufman S, Faust J, Rowan C, Dwyer E, Nichol JL, Grasel T, Wilson J, Steinbrink R, Hecht R, Winters D, Boone T, Hunt P (1995) Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice. Blood 86:4486–4492

    PubMed  CAS  Google Scholar 

  • Horikawa Y, Matsumura I, Hashimoto K, Shiraga M, Kosugi S, Tadokoro S, Kato T, Miyazaki H, Tomiyama Y, Kurata Y, Matsuzawa Y, Kanakura Y (1997) Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia. Blood 90:4031–4038

    PubMed  CAS  Google Scholar 

  • Ichikawa M, Asai T, Saito T, Seo S, Yamazaki I, Yamagata T, Mitani K, Chiba S, Ogawa S, Kurokawa M, Hirai H (2004) AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 10:299–304

    Article  PubMed  CAS  Google Scholar 

  • Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, Hara T (1999) Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci USA 96:3132–3136

    Article  PubMed  CAS  Google Scholar 

  • Jacobsen P, Hauge M, Henningsen K, Hobolth N, Mikkelsen M, Philip J (1973) An (11;21) translocation in four generations with chromosome 11 abnormalities in the offspring. A clinical, cytogenetical, and gene marker study. Hum Hered 23:568–585

    Article  PubMed  CAS  Google Scholar 

  • Jain S, Harris J, Ware J (2010) Platelets: linking hemostasis and cancer. Arterioscler Thromb Vasc Biol 30:2362–2367

    Article  PubMed  CAS  Google Scholar 

  • James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148

    Article  PubMed  CAS  Google Scholar 

  • Kajiwara M, Nonoyama S, Eguchi M, Morio T, Imai K, Okawa H, Kaneko M, Sako M, Ohga S, Maeda M, Hibi S, Hashimito H, Shibuya A, Ochs HD, Nakahata T, Yata JI (1999) WASP is involved in proliferation and differentiation of human haemopoietic progenitors in vitro. Br J Haematol 107:254–262

    Article  PubMed  CAS  Google Scholar 

  • Kakumitsu H, Kamezaki K, Shimoda K, Karube K, Haro T, Numata A, Shide K, Matsuda T, Oshima K, Harada M (2005) Transgenic mice overexpressing murine thrombopoietin develop myelofibrosis and osteosclerosis. Leuk Res 29:761–769

    Article  PubMed  CAS  Google Scholar 

  • Kato K, Martinez C, Russell S, Nurden P, Nurden A, Fiering S, Ware J (2004) Genetic deletion of mouse platelet glycoprotein Ibbeta produces a Bernard-Soulier phenotype with increased alpha-granule size. Blood 104:2339–2344

    Article  PubMed  CAS  Google Scholar 

  • Katsman Y, Foo AH, Leontyev D, Branch DR (2010) Improved mouse models for the study of treatment modalities for immune-mediated platelet destruction. Transfusion 50:1285–1294

    Article  PubMed  CAS  Google Scholar 

  • Kauppi M, Murphy JM, de Graaf CA, Hyland CD, Greig KT, Metcalf D, Hilton AA, Nicola NA, Kile BT, Hilton DJ, Alexander WS (2008) Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl−/− mice. Blood 112:3148–3153

    Article  PubMed  CAS  Google Scholar 

  • Kaushansky K (2008) Historical review: megakaryopoiesis and thrombopoiesis. Blood 111:981–986

    Article  PubMed  CAS  Google Scholar 

  • Kaushansky K (2009) Molecular mechanisms of thrombopoietin signaling. J Thromb Haemost 7(Suppl 1):235–238

    Article  PubMed  CAS  Google Scholar 

  • Kaushansky K, Broudy VC, Grossmann A, Humes J, Lin N, Ren HP, Bailey MC, Papayannopoulou T, Forstrom JW, Sprugel KH (1995) Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy. J Clin Invest 96:1683–1687

    Article  PubMed  CAS  Google Scholar 

  • Kawada H, Ito T, Pharr PN, Spyropoulos DD, Watson DK, Ogawa M (2001) Defective megakaryopoiesis and abnormal erythroid development in Fli-1 gene-targeted mice. Int J Hematol 73:463–468

    Article  PubMed  CAS  Google Scholar 

  • Kimura S, Roberts AW, Metcalf D, Alexander WS (1998) Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci USA 95:1195–1200

    Article  PubMed  CAS  Google Scholar 

  • Kirsammer G, Jilani S, Liu H, Davis E, Gurbuxani S, Le Beau MM, Crispino JD (2008) Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 111:767–775

    Article  PubMed  CAS  Google Scholar 

  • Klusmann JH, Godinho FJ, Heitmann K, Maroz A, Koch ML, Reinhardt D, Orkin SH, Li Z (2010) Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. Genes Dev 24:1659–1672

    Article  PubMed  CAS  Google Scholar 

  • Kondo T, Okabe M, Sanada M, Kurosawa M, Suzuki S, Kobayashi M, Hosokawa M, Asaka M (1998) Familial essential thrombocythemia associated with one-base deletion in the 5’-untranslated region of the thrombopoietin gene. Blood 92:1091–1096

    PubMed  CAS  Google Scholar 

  • Koppikar P, Abdel-Wahab O, Hedvat C, Marubayashi S, Patel J, Goel A, Kucine N, Gardner JR, Combs AP, Vaddi K, Haley PJ, Burn TC, Rupar M, Bromberg JF, Heaney ML, de Stanchina E, Fridman JS, Levine RL (2010) Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis. Blood 115:2919–2927

    Article  PubMed  CAS  Google Scholar 

  • Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779–1790

    Article  PubMed  CAS  Google Scholar 

  • Kruse EA, Loughran SJ, Baldwin TM, Josefsson EC, Ellis S, Watson DK, Nurden P, Metcalf D, Hilton DJ, Alexander WS, Kile BT (2009) Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage. Proc Natl Acad Sci USA 106:13814–13819

    Article  PubMed  CAS  Google Scholar 

  • Kundu M, Compton S, Garrett-Beal L, Stacy T, Starost MF, Eckhaus M, Speck NA, Liu PP (2005) Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma. Blood 106:3621–3624

    Article  PubMed  CAS  Google Scholar 

  • Kunishima S, Saito H (2010) Advances in the understanding of MYH9 disorders. Curr Opin Hematol 17:405–410

    Article  PubMed  CAS  Google Scholar 

  • Lacout C, Pisani DF, Tulliez M, Gachelin FM, Vainchenker W, Villeval JL (2006) JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood 108:1652–1660

    Article  PubMed  CAS  Google Scholar 

  • Lannutti BJ, Epp A, Roy J, Chen J, Josephson NC (2009) Incomplete restoration of Mpl expression in the mpl−/− mouse produces partial correction of the stem cell-repopulating defect and paradoxical thrombocytosis. Blood 113:1778–1785

    Article  PubMed  CAS  Google Scholar 

  • Leon C, Eckly A, Hechler B, Aleil B, Freund M, Ravanat C, Jourdain M, Nonne C, Weber J, Tiedt R, Gratacap MP, Severin S, Cazenave JP, Lanza F, Skoda R, Gachet C (2007) Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion. Blood 110:3183–3191

    Article  PubMed  CAS  Google Scholar 

  • Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–397

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, Orkin SH (2005) Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 37:613–619

    Article  PubMed  CAS  Google Scholar 

  • Li J, Spensberger D, Ahn JS, Anand S, Beer PA, Ghevaert C, Chen E, Forrai A, Scott LM, Ferreira R, Campbell PJ, Watson SP, Liu P, Erber WN, Huntly BJ, Ottersbach K, Green AR (2010) JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood 116:1528–1538

    Article  PubMed  CAS  Google Scholar 

  • Liu K, Martini M, Rocca B, Amos CI, Teofili L, Giona F, Ding J, Komatsu H, Larocca LM, Skoda RC (2009) Evidence for a founder effect of the MPL-S505 N mutation in eight Italian pedigrees with hereditary thrombocythemia. Haematologica 94:1368–1374

    Article  PubMed  CAS  Google Scholar 

  • Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC (1998) Bernard-Soulier syndrome. Blood 91:4397–4418

    PubMed  CAS  Google Scholar 

  • Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X, Bouman D, Li Y, Mehta PK, Nizetic D, Kaneko Y, Chan GC, Chan LC, Squire J, Scherer SW, Hitzler JK (2001) Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220–221

    Article  PubMed  CAS  Google Scholar 

  • Majewski IJ, Metcalf D, Mielke LA, Krebs DL, Ellis S, Carpinelli MR, Mifsud S, Di Rago L, Corbin J, Nicola NA, Hilton DJ, Alexander WS (2006) A mutation in the translation initiation codon of Gata-1 disrupts megakaryocyte maturation and causes thrombocytopenia. Proc Natl Acad Sci USA 103:14146–14151

    Article  PubMed  CAS  Google Scholar 

  • Majewski IJ, Blewitt ME, de Graaf CA, McManus EJ, Bahlo M, Hilton AA, Hyland CD, Smyth GK, Corbin JE, Metcalf D, Alexander WS, Hilton DJ (2008) Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol 6:e93

    Article  PubMed  CAS  Google Scholar 

  • Majewski IJ, Ritchie ME, Phipson B, Corbin J, Pakusch M, Ebert A, Busslinger M, Koseki H, Hu Y, Smyth GK, Alexander WS, Hilton DJ, Blewitt ME (2010) Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 116:731–739

    Article  PubMed  CAS  Google Scholar 

  • Malinge S, Ragu C, Della-Valle V, Pisani D, Constantinescu SN, Perez C, Villeval JL, Reinhardt D, Landman-Parker J, Michaux L, Dastugue N, Baruchel A, Vainchenker W, Bourquin JP, Penard-Lacronique V, Bernard OA (2008) Activating mutations in human acute megakaryoblastic leukemia. Blood 112:4220–4226

    Article  PubMed  CAS  Google Scholar 

  • Malinge S, Izraeli S, Crispino JD (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113:2619–2628

    Article  PubMed  CAS  Google Scholar 

  • Marathe BM, Prislovsky A, Astrakhan A, Rawlings DJ, Wan JY, Strom TS (2009) Antiplatelet antibodies in WASP(-) mice correlate with evidence of increased in vivo platelet consumption. Exp Hematol 37:1353–1363

    Article  PubMed  CAS  Google Scholar 

  • Marty C, Lacout C, Martin A, Hasan S, Jacquot S, Birling MC, Vainchenker W, Villeval JL (2010) Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice. Blood 116:783–787

    Article  PubMed  CAS  Google Scholar 

  • Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT (2007) Programmed anuclear cell death delimits platelet life span. Cell 128:1173–1186

    Article  PubMed  CAS  Google Scholar 

  • Matsushita T, Hayashi H, Kunishima S, Hayashi M, Ikejiri M, Takeshita K, Yuzawa Y, Adachi T, Hirashima K, Sone M, Yamamoto K, Takagi A, Katsumi A, Kawai K, Nezu T, Takahashi M, Nakashima T, Naoe T, Kojima T, Saito H (2004) Targeted disruption of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia with different organ involvement: hematological, nephrological, and otological studies of heterozygous KO mice. Biochem Biophys Res Commun 325:1163–1171

    Article  PubMed  CAS  Google Scholar 

  • McKenzie SE, Reilly MP (2004) Heparin-induced thrombocytopenia and other immune thrombocytopenias: lessons from mouse models. Semin Thromb Hemost 30:559–568

    Article  PubMed  CAS  Google Scholar 

  • McMorran BJ, Marshall VM, de Graaf C, Drysdale KE, Shabbar M, Smyth GK, Corbin JE, Alexander WS, Foote SJ (2009) Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 323:797–800

    Article  PubMed  CAS  Google Scholar 

  • Mercher T, Coniat MB, Monni R, Mauchauffe M, Nguyen Khac F, Gressin L, Mugneret F, Leblanc T, Dastugue N, Berger R, Bernard OA (2001) Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci USA 98:5776–5779

    Article  PubMed  CAS  Google Scholar 

  • Mercher T, Raffel GD, Moore SA, Cornejo MG, Baudry-Bluteau D, Cagnard N, Jesneck JL, Pikman Y, Cullen D, Williams IR, Akashi K, Shigematsu H, Bourquin JP, Giovannini M, Vainchenker W, Levine RL, Lee BH, Bernard OA, Gilliland DG (2009) The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J Clin Invest 119:852–864

    PubMed  CAS  Google Scholar 

  • Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, Shigesada K, Ito Y, Benson KF, Raskind WH, Rossier C, Antonarakis SE, Israels S, McNicol A, Weiss H, Horwitz M, Scott HS (2002) In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 99:1364–1372

    Article  PubMed  CAS  Google Scholar 

  • Miller JL, Lyle VA, Cunningham D (1992) Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard-Soulier disease. Blood 79:439–446

    PubMed  CAS  Google Scholar 

  • Molineux G, Hartley CA, McElroy P, McCrea C, McNiece IK (1996) Megakaryocyte growth and development factor stimulates enhanced platelet recovery in mice after bone marrow transplantation. Blood 88:1509–1514

    PubMed  CAS  Google Scholar 

  • Moliterno AR, Hankins WD, Spivak JL (1998) Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. N Engl J Med 338:572–580

    Article  PubMed  CAS  Google Scholar 

  • Moliterno AR, Williams DM, Gutierrez-Alamillo LI, Salvatori R, Ingersoll RG, Spivak JL (2004) Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis. Proc Natl Acad Sci USA 101:11444–11447

    Article  PubMed  CAS  Google Scholar 

  • Moussa O, LaRue AC, Abangan RS Jr, Williams CR, Zhang XK, Masuya M, Gong YZ, Spyropoulos DD, Ogawa M, Gilkeson G, Watson DK (2010) Thrombocytopenia in mice lacking the carboxy-terminal regulatory domain of the Ets transcription factor Fli1. Mol Cell Biol 30:5194–5206

    Article  PubMed  CAS  Google Scholar 

  • Mullally A, Lane SW, Ball B, Megerdichian C, Okabe R, Al-Shahrour F, Paktinat M, Haydu JE, Housman E, Lord AM, Wernig G, Kharas MG, Mercher T, Kutok JL, Gilliland DG, Ebert BL (2010) Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 17:584–596

    Article  PubMed  CAS  Google Scholar 

  • Ng AP, Hyland CD, Metcalf D, Carmichael CL, Loughran SJ, Di Rago L, Kile BT, Alexander WS (2010) Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome. Blood 115:3966–3969

    Article  PubMed  CAS  Google Scholar 

  • Notarangelo LD, Miao CH, Ochs HD (2008) Wiskott-Aldrich syndrome. Curr Opin Hematol 15:30–36

    Article  PubMed  CAS  Google Scholar 

  • Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR (1996) AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84:321–330

    Article  PubMed  CAS  Google Scholar 

  • Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, Steensma DP, Elliott MA, Wolanskyj AP, Hogan WJ, McClure RF, Litzow MR, Gilliland DG, Tefferi A (2006) MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108:3472–3476

    Article  PubMed  CAS  Google Scholar 

  • Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, Gresele P, Lethagen S, Fabris F, Dufour C, Granata A, Doubek M, Pecoraro C, Koivisto PA, Heller PG, Iolascon A, Alvisi P, Schwabe D, De Candia E, Rocca B, Russo U, Ramenghi U, Noris P, Seri M, Balduini CL, Savoia A (2008) Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat 29:409–417

    Article  PubMed  CAS  Google Scholar 

  • Pevny L, Simon MC, Robertson E, Klein WH, Tsai SF, D’Agati V, Orkin SH, Costantini F (1991) Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349:257–260

    Article  PubMed  CAS  Google Scholar 

  • Pevny L, Lin CS, D’Agati V, Simon MC, Orkin SH, Costantini F (1995) Development of hematopoietic cells lacking transcription factor GATA-1. Development 121:163–172

    PubMed  CAS  Google Scholar 

  • Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, Cuker A, Wernig G, Moore S, Galinsky I, DeAngelo DJ, Clark JJ, Lee SJ, Golub TR, Wadleigh M, Gilliland DG, Levine RL (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3:e270

    Article  PubMed  CAS  Google Scholar 

  • Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel JB (2009) Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 113:3154–3160

    Article  PubMed  CAS  Google Scholar 

  • Prislovsky A, Marathe B, Hosni A, Bolen AL, Nimmerjahn F, Jackson CW, Weiman D, Strom TS (2008) Rapid platelet turnover in WASP(-) mice correlates with increased ex vivo phagocytosis of opsonized WASP(-) platelets. Exp Hematol 36:609–623

    Article  PubMed  CAS  Google Scholar 

  • Putz G, Rosner A, Nuesslein I, Schmitz N, Buchholz F (2006) AML1 deletion in adult mice causes splenomegaly and lymphomas. Oncogene 25:929–939

    Article  PubMed  CAS  Google Scholar 

  • Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J, Mansson R, Thoren LA, Ekblom M, Alexander WS, Jacobsen SE (2007) Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 1:671–684

    Article  PubMed  CAS  Google Scholar 

  • Raskind WH, Niakan KK, Wolff J, Matsushita M, Vaughan T, Stamatoyannopoulos G, Watanabe C, Rios J, Ochs HD (2000) Mapping of a syndrome of X-linked thrombocytopenia with Thalassemia to band Xp11–12: further evidence of genetic heterogeneity of X-linked thrombocytopenia. Blood 95:2262–2268

    PubMed  CAS  Google Scholar 

  • Raslova H, Komura E, Le Couedic JP, Larbret F, Debili N, Feunteun J, Danos O, Albagli O, Vainchenker W, Favier R (2004) FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia. J Clin Invest 114:77–84

    PubMed  CAS  Google Scholar 

  • Sabri S, Foudi A, Boukour S, Franc B, Charrier S, Jandrot-Perrus M, Farndale RW, Jalil A, Blundell MP, Cramer EM, Louache F, Debili N, Thrasher AJ, Vainchenker W (2006) Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment. Blood 108:134–140

    Article  PubMed  CAS  Google Scholar 

  • Schafer AI (2004) Thrombocytosis. N Engl J Med 350:1211–1219

    Article  PubMed  CAS  Google Scholar 

  • Scott LM, Scott MA, Campbell PJ, Green AR (2006) Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood 108:2435–2437

    Article  PubMed  CAS  Google Scholar 

  • Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR (2007) JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 356:459–468

    Article  PubMed  CAS  Google Scholar 

  • Shide K, Shimoda HK, Kumano T, Karube K, Kameda T, Takenaka K, Oku S, Abe H, Katayose KS, Kubuki Y, Kusumoto K, Hasuike S, Tahara Y, Nagata K, Matsuda T, Ohshima K, Harada M, Shimoda K (2008) Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia 22:87–95

    Article  PubMed  CAS  Google Scholar 

  • Shimizu R, Ohneda K, Engel JD, Trainor CD, Yamamoto M (2004) Transgenic rescue of GATA-1-deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia. Blood 103:2560–2567

    Article  PubMed  CAS  Google Scholar 

  • Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH (1997) A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J 16:3965–3973

    Article  PubMed  CAS  Google Scholar 

  • Skoda RC (2009) Thrombocytosis. Hematology Am Soc Hematol Educ Program 2009:159–167

    Google Scholar 

  • Snapper SB, Rosen FS, Mizoguchi E, Cohen P, Khan W, Liu CH, Hagemann TL, Kwan SP, Ferrini R, Davidson L, Bhan AK, Alt FW (1998) Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9:81–91

    Article  PubMed  CAS  Google Scholar 

  • Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23:166–175

    Article  PubMed  CAS  Google Scholar 

  • Spyropoulos DD, Pharr PN, Lavenburg KR, Jackers P, Papas TS, Ogawa M, Watson DK (2000) Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Mol Cell Biol 20:5643–5652

    Article  PubMed  CAS  Google Scholar 

  • Stankiewicz MJ, Crispino JD (2009) ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood 113:3337–3347

    Article  PubMed  CAS  Google Scholar 

  • Starck J, Weiss-Gayet M, Gonnet C, Guyot B, Vicat JM, Morle F (2010) Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation. Blood 116:4795–4805

    Article  PubMed  CAS  Google Scholar 

  • Stoffel R, Wiestner A, Skoda RC (1996) Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. Blood 87:567–573

    PubMed  CAS  Google Scholar 

  • Strassel C, Nonne C, Eckly A, David T, Leon C, Freund M, Cazenave JP, Gachet C, Lanza F (2007) Decreased thrombotic tendency in mouse models of the Bernard-Soulier syndrome. Arterioscler Thromb Vasc Biol 27:241–247

    Article  PubMed  CAS  Google Scholar 

  • Strassel C, Eckly A, Leon C, Petitjean C, Freund M, Cazenave JP, Gachet C, Lanza F (2009) Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome. Haematologica 94:800–810

    Article  PubMed  CAS  Google Scholar 

  • Sun W, Downing JR (2004) Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors. Blood 104:3565–3572

    Article  PubMed  CAS  Google Scholar 

  • Takahashi S, Onodera K, Motohashi H, Suwabe N, Hayashi N, Yanai N, Nabesima Y, Yamamoto M (1997) Arrest in primitive erythroid cell development caused by promoter-specific disruption of the GATA-1 gene. J Biol Chem 272:12611–12615

    Article  PubMed  CAS  Google Scholar 

  • Teofili L, Giona F, Martini M, Cenci T, Guidi F, Torti L, Palumbo G, Amendola A, Foa R, Larocca LM (2007) Markers of myeloproliferative diseases in childhood polycythemia vera and essential thrombocythemia. J Clin Oncol 25:1048–1053

    Article  PubMed  CAS  Google Scholar 

  • Tiedt R, Hao-Shen H, Sobas MA, Looser R, Dirnhofer S, Schwaller J, Skoda RC (2008) Ratio of mutant JAK2–V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 111:3931–3940

    Article  PubMed  CAS  Google Scholar 

  • Tiedt R, Coers J, Ziegler S, Wiestner A, Hao-Shen H, Bornmann C, Schenkel J, Karakhanova S, de Sauvage FJ, Jackson CW, Skoda RC (2009) Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes. Blood 113:1768–1777

    Article  PubMed  CAS  Google Scholar 

  • Tong W, Lodish HF (2004) Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. J Exp Med 200:569–580

    Article  PubMed  Google Scholar 

  • Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, Norton A, Vyas P, Roberts I (2008) Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 112:4507–4511

    Article  PubMed  CAS  Google Scholar 

  • Ulich TR, del Castillo J, Yin S, Swift S, Padilla D, Senaldi G, Bennett L, Shutter J, Bogenberger J, Sun D et al (1995) Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Blood 86:971–976

    PubMed  CAS  Google Scholar 

  • Vannucchi AM, Barbui T (2007) Thrombocytosis and thrombosis. Hematology Am Soc Hematol Educ Program 2007:363–370

    Google Scholar 

  • Velazquez L, Cheng AM, Fleming HE, Furlonger C, Vesely S, Bernstein A, Paige CJ, Pawson T (2002) Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J Exp Med 195:1599–1611

    Article  PubMed  CAS  Google Scholar 

  • Vettore S, Scandellari R, Moro S, Lombardi AM, Scapin M, Randi ML, Fabris F (2008) Novel point mutation in a leucine-rich repeat of the GPIbalpha chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant. Haematologica 93:1743–1747

    Article  PubMed  CAS  Google Scholar 

  • Vigon I, Mornon JP, Cocault L, Mitjavila MT, Tambourin P, Gisselbrecht S, Souyri M (1992) Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc Natl Acad Sci USA 89:5640–5644

    Article  PubMed  CAS  Google Scholar 

  • Villeval JL, Cohen-Solal K, Tulliez M, Giraudier S, Guichard J, Burstein SA, Cramer EM, Vainchenker W, Wendling F (1997) High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood 90:4369–4383

    PubMed  CAS  Google Scholar 

  • Vyas P, Ault K, Jackson CW, Orkin SH, Shivdasani RA (1999) Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 93:2867–2875

    PubMed  CAS  Google Scholar 

  • Walters DK, Mercher T, Gu TL, O’Hare T, Tyner JW, Loriaux M, Goss VL, Lee KA, Eide CA, Wong MJ, Stoffregen EP, McGreevey L, Nardone J, Moore SA, Crispino J, Boggon TJ, Heinrich MC, Deininger MW, Polakiewicz RD, Gilliland DG, Druker BJ (2006) Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10:65–75

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA (1996) Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci USA 93:3444–3449

    Article  PubMed  CAS  Google Scholar 

  • Ware J, Russell S, Ruggeri ZM (2000) Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc Natl Acad Sci USA 97:2803–2808

    Article  PubMed  CAS  Google Scholar 

  • Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32:148–152

    Article  PubMed  CAS  Google Scholar 

  • Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG (2006) Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 107:4274–4281

    Article  PubMed  CAS  Google Scholar 

  • Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC (1998) An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat Genet 18:49–52

    Article  PubMed  CAS  Google Scholar 

  • Wiskott A (1936) Familiarer, angeborener morbus werlhofii. Monatsschr Kinderheilkd 68:212–216

    Google Scholar 

  • Xing S, Wanting TH, Zhao W, Ma J, Wang S, Xu X, Li Q, Fu X, Xu M, Zhao ZJ (2008) Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood 111:5109–5117

    Article  PubMed  CAS  Google Scholar 

  • Yamashita N, Osato M, Huang L, Yanagida M, Kogan SC, Iwasaki M, Nakamura T, Shigesada K, Asou N, Ito Y (2005) Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice. Br J Haematol 131:495–507

    Article  PubMed  CAS  Google Scholar 

  • Yan XQ, Lacey D, Fletcher F, Hartley C, McElroy P, Sun Y, Xia M, Mu S, Saris C, Hill D, Hawley RG, McNiece IK (1995) Chronic exposure to retroviral vector encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice. Blood 86:4025–4033

    PubMed  CAS  Google Scholar 

  • Yan XQ, Lacey D, Hill D, Chen Y, Fletcher F, Hawley RG, McNiece IK (1996) A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. Blood 88:402–409

    PubMed  CAS  Google Scholar 

  • Yan XQ, Lacey DL, Saris C, Mu S, Hill D, Hawley RG, Fletcher FA (1999) Ectopic overexpression of c-mpl by retroviral-mediated gene transfer suppressed megakaryopoiesis but enhanced erythropoiesis in mice. Exp Hematol 27:1409–1417

    Article  PubMed  CAS  Google Scholar 

  • Zaleskas VM, Krause DS, Lazarides K, Patel N, Hu Y, Li S, Van Etten RA (2006) Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F. PLoS One 1:e18

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Shehabeldin A, da Cruz LA, Butler J, Somani AK, McGavin M, Kozieradzki I, dos Santos AO, Nagy A, Grinstein S, Penninger JM, Siminovitch KA (1999) Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J Exp Med 190:1329–1342

    Article  PubMed  CAS  Google Scholar 

  • Zhou W, Toombs CF, Zou T, Guo J, Robinson MO (1997) Transgenic mice overexpressing human c-mpl ligand exhibit chronic thrombocytosis and display enhanced recovery from 5-fluorouracil or antiplatelet serum treatment. Blood 89:1551–1559

    PubMed  CAS  Google Scholar 

  • Zhu Q, Watanabe C, Liu T, Hollenbaugh D, Blaese RM, Kanner SB, Aruffo A, Ochs HD (1997) Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. Blood 90:2680–2689

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors’ research is supported by Research Grants (including Program Grant 461219), Fellowships, and an Independent Research Institutes Support Scheme Grant from the Australian National Health and Medical Research Council of Australia (NHMRC), the Australian Cancer Research Fund, the Leukaemia Foundation of Australia, and a Victorian State Government Operational Infrastructure Support grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Warren S. Alexander.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carmichael, C.L., Alexander, W.S. Mouse models of diseases of megakaryocyte and platelet homeostasis. Mamm Genome 22, 449–465 (2011). https://doi.org/10.1007/s00335-011-9336-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-011-9336-4

Keywords

Navigation