Systems Biology of Megakaryocytes

  • Alexis Kaushansky
  • Kenneth KaushanskyEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 844)


The molecular pathways that regulate megakaryocyte production have historically been identified through multiple candidate gene approaches. Several transcription factors critical for generating megakaryocytes were identified by promoter analysis of megakaryocyte-specific genes, and their biological roles then verified by gene knockout studies; for example, GATA-1, NF-E2, and RUNX1 were identified in this way. In contrast, other transcription factors important for megakaryopoiesis were discovered through a systems approach; for example, c-Myb was found to be critical for the erythroid versus megakaryocyte lineage decision by genome-wide loss-of-function studies. The regulation of the levels of these transcription factors is, for the most part, cell intrinsic, although that assumption has recently been challenged. Epigenetics also impacts megakaryocyte gene expression, mediated by histone acetylation and methylation. Several cytokines have been identified to regulate megakaryocyte survival, proliferation, and differentiation, most prominent of which is thrombopoietin. Upon binding to its receptor, the product of the c-Mpl proto-oncogene, thrombopoietin induces a conformational change that activates a number of secondary messengers that promote cell survival, proliferation, and differentiation, and down-modulate receptor signaling. Among the best studied are the signal transducers and activators of transcription (STAT) proteins; phosphoinositol-3-kinase; mitogen-activated protein kinases; the phosphatases PTEN, SHP1, SHP2, and SHIP1; and the suppressors of cytokine signaling (SOCS) proteins. Additional signals activated by these secondary mediators include mammalian target of rapamycin; β(beta)-catenin; the G proteins Rac1, Rho, and CDC42; several transcription factors, including hypoxia-inducible factor 1α(alpha), the homeobox-containing proteins HOXB4 and HOXA9, and a number of signaling mediators that are reduced, including glycogen synthase kinase 3α(alpha) and the FOXO3 family of forkhead proteins. More recently, systematic interrogation of several aspects of megakaryocyte formation have been conducted, employing genomics, proteomics, and chromatin immunoprecipitation (ChIP) analyses, among others, and have yielded many previously unappreciated signaling mechanisms that regulate megakaryocyte lineage determination, proliferation, and differentiation. This chapter focuses on these pathways in normal and neoplastic megakaryopoiesis, and suggests areas that are ripe for further study.


Megakaryocytes Platelets Systems biology Protein array Genomics Signal transduction Transcription factors Thrombopoietin Cell proliferation Endomitosis 


  1. 1.
    Yousuf O, Bhatt DL. The evolution of antiplatelet therapy in cardiovascular disease. Nat Rev Cardiol. 2011;8:547–59.PubMedCrossRefGoogle Scholar
  2. 2.
    Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost. 2011;105(Suppl 1):S13–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Semple JW, Italiano JE, Jr., Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11:264–74.PubMedCrossRefGoogle Scholar
  4. 4.
    Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011;11:123–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 1997;16:3965–73.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Lemarchandel V, Ghysdael J, Mignotte V, Rahuel C, Romeo PH. GATA and Ets cis-acting sequences mediate megakaryocyte-specific expression. Mol Cell Biol. 1993;13:668–76.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Bastian LS, Kwiatkowski BA, Breininger J, Danner S, Roth G. Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1. Blood. 1999;93:2637–44.PubMedGoogle Scholar
  8. 8.
    Furihata K, Kunicki TJ. Characterization of human glycoprotein VI gene 5′ regulatory and promoter regions. Arterioscler Thromb Vasc Biol. 2002;22:1733–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Lacabaratz-Porret C, et al. Biogenesis of endoplasmic reticulum proteins involved in Ca2+ signalling during megakaryocytic differentiation: an in vitro study. Biochem J. 2000;350(Pt 3):723–34.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Muntean AG, Crispino JD. Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development. Blood. 2005;106:1223–31.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Andrews NC, Erdjument-Bromage H, Davidson MB, Tempst P, Orkin SH. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature. 1993;362:722–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Bean TL, Ney PA. Multiple regions of p45 NF-E2 are required for beta-globin gene expression in erythroid cells. Nucleic Acids Res. 1997;25:2509–15.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Shivdasani RA, et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell. 1995;81:695–704.PubMedCrossRefGoogle Scholar
  14. 14.
    Lecine P, Italiano JE Jr, Kim SW, Villeval JL, Shivdasani RA. Hematopoietic-specific beta 1 tubulin participates in a pathway of platelet biogenesis dependent on the transcription factor NF-E2. Blood. 2000;96:1366–73.PubMedGoogle Scholar
  15. 15.
    Deveaux S, et al. p45 NF-E2 regulates expression of thromboxane synthase in megakaryocytes. EMBO J. 1997;16:5654–61.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Raslova H, et al. FLI-1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia. J Clin Invest. 2004;114:77–84.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Moussa O, et al. Thrombocytopenia in mice lacking the carboxy-terminal regulatory domain of the Ets transcription factor Fli1. Mol Cell Biol. 2012;30:5194–206.CrossRefGoogle Scholar
  18. 18.
    Kruse EA, et al. Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage. Proc Natl Acad Sci U S A. 2009;106:13814–9.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Friedman AD. Cell cycle and developmental control of hematopoiesis by Runx1. J Cell Physiol. 2009;219:520–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Wei Q, Paterson BM. Regulation of MyoD function in the dividing myoblast. FEBS Lett. 2001;490:171–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Freson K, et al. Molecular cloning and characterization of the GATA1 cofactor human FOG1 and assessment of its binding to GATA1 proteins carrying D218 substitutions. Hum Genet. 2003;112:42–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Gaines P, Geiger JN, Knudsen G, Seshasayee D, Wojchowski DM. GATA-1- and FOG-dependent activation of megakaryocytic alpha IIB gene expression. J Biol Chem. 2000;275:34114–21.PubMedCrossRefGoogle Scholar
  23. 23.
    Freson K, et al. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood. 2001;98:85–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Wang Y, et al. Pleiotropic platelet defects in mice with disrupted FOG1-NuRD interaction. Blood. 2011;118:6183–91.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Thomas M, Lieberman J, Lal A. Desperately seeking microRNA targets. Nat Struct Mol Biol. 2010;17:1169–74.PubMedCrossRefGoogle Scholar
  26. 26.
    O’Connell RM, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205:585–94.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Lu J, et al. MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell. 2008;14:843–53.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Emambokus N, et al. Progression through key stages of haemopoiesis is dependent on distinct threshold levels of c-Myb. EMBO J. 2003;22:4478–88.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Navarro F, et al. miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53. Blood. 2009;114:2181–92.PubMedCrossRefGoogle Scholar
  30. 30.
    Ben-Ami O, Pencovich N, Lotem J, Levanon D, Groner Y. A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis. Proc Natl Acad Sci U S A. 2009;106:238–43.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Fuhrken PG, et al. Gene Ontology-driven transcriptional analysis of CD34 + cell-initiated megakaryocytic cultures identifies new transcriptional regulators of megakaryopoiesis. Physiol Genomics. 2008;33:159–69.PubMedCrossRefGoogle Scholar
  32. 32.
    Li L, et al. A requirement for Lim domain binding protein 1 in erythropoiesis. J Exp Med. 2010;207:2543–50.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Krumsiek J, Marr C, Schroeder T, Theis FJ. Hierarchical differentiation of myeloid progenitors is encoded in the transcription factor network. PLoS ONE. 2011;6:e22649.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Garzon R, et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci U S A. 2006;103:5078–83.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Opalinska JB, et al. MicroRNA expression in maturing murine megakaryocytes. Blood. 2010;116:e128–38.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Hussein K, et al. MicroRNA expression profiling of megakaryocytes in primary myelofibrosis and essential thrombocythemia. Platelets. 2009;20:391–400.PubMedCrossRefGoogle Scholar
  37. 37.
    Girardot M, et al. miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets. Blood. 2010;116:437–45.PubMedCrossRefGoogle Scholar
  38. 38.
    Gannon AM, Kinsella BT. Regulation of the human thromboxane A2 receptor gene by Sp1, Egr1, NF-E2, GATA-1, and Ets-1 in megakaryocytes. J Lipid Res. 2008;49:2590–604.PubMedCrossRefGoogle Scholar
  39. 39.
    Eisbacher M, et al. Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding. Mol Cell Biol. 2003;23:3427–41.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Komor M, et al. Transcriptional profiling of human hematopoiesis during in vitro lineage-specific differentiation. Stem Cells. 2005;23:1154–69.PubMedCrossRefGoogle Scholar
  41. 41.
    Chen C, et al. A systems-biology analysis of isogenic megakaryocytic and granulocytic cultures identifies new molecular components of megakaryocytic apoptosis. BMC Genomics. 2007;8:384.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Tijssen MR, et al. Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators. Dev Cell. 2011;20:597–609.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Paul DS, et al. Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits. PLoS Genet. 2011;7:e1002139.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Vyas P, Norris FA, Joseph R, Majerus PW, Orkin SH. Inositol polyphosphate 4-phosphatase type I regulates cell growth downstream of transcription factor GATA-1. Proc Natl Acad Sci U S A. 2000;97:13696–701.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Rollins BJ. Chemokines. Blood. 1997;90:909–28.PubMedGoogle Scholar
  46. 46.
    Nagasawa T, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382:635–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Ma Q, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998;95:9448–53.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Wang JF, Liu ZY, Groopman JE. The alpha-chemokine receptor CXCR4 is expressed on the megakaryocytic lineage from progenitor to platelets and modulates migration and adhesion. Blood. 1998;92:756–64.PubMedGoogle Scholar
  49. 49.
    Hamada T, et al. Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med. 1998;188:539–48.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Hodohara K, Fujii N, Yamamoto N, Kaushansky K. Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK). Blood. 2000;95:769–75.PubMedGoogle Scholar
  51. 51.
    Avecilla ST, et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med. 2004;10:64–71.PubMedCrossRefGoogle Scholar
  52. 52.
    Staerk J, et al. Orientation-specific signalling by thrombopoietin receptor dimers. EMBO J. 2011;30:4398–413.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Kaser A, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001;98:2720–25.PubMedCrossRefGoogle Scholar
  54. 54.
    Negrotto S, et al. Expression and functionality of type I interferon receptor in the megakaryocytic lineage. J Thromb Haemost. 2011;9:2477–85.PubMedCrossRefGoogle Scholar
  55. 55.
    Huang Z, et al. STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. J Clin Invest. 2007;117:3890–9.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Nurden P, Nurden AT. Congenital disorders associated with platelet dysfunctions. Thromb Haemost. 2008;99:253–63.PubMedGoogle Scholar
  57. 57.
    Fox NE, Kaushansky K. Engagement of integrin alpha4beta1 enhances thrombopoietin-induced megakaryopoiesis. Exp Hematol. 2005;33:94–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Larson MK, Watson SP. Regulation of proplatelet formation and platelet release by integrin alpha IIb beta3. Blood. 2006;108:1509–14.PubMedCrossRefGoogle Scholar
  59. 59.
    Nuyttens BP, Thijs T, Deckmyn H, Broos K. Platelet adhesion to collagen. Thromb Res. 2011;127(Suppl 2):S26–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Margarucci L, et al. Collagen stimulation of platelets induces a rapid spatial response of cAMP and cGMP signaling scaffolds. Mol Biosyst. 2011;7:2311–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Jung SM, Moroi M. Platelet glycoprotein VI. Adv Exp Med Biol. 2008;640:53–63.PubMedCrossRefGoogle Scholar
  62. 62.
    Akbar H, et al. Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation. PLoS ONE. 2011;6:e22117.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Macaulay IC, et al. Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Blood. 2007;109:3260–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Senis YA, et al. A comprehensive proteomics and genomics analysis reveals novel transmembrane proteins in human platelets and mouse megakaryocytes including G6b-B, a novel immunoreceptor tyrosine-based inhibitory motif protein. Mol Cell Proteomics. 2007;6:548–64.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Mori J, et al. G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2. J Biol Chem. 2008;283:35419–27.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Kirito K, Kaushansky K. Transcriptional regulation of megakaryopoiesis: thrombopoietin signaling and nuclear factors. Curr Opin Hematol. 2006;13:151–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Kirito K, et al. A functional role of Stat3 in in vivo megakaryopoiesis. Blood. 2002;99:3220–27.PubMedCrossRefGoogle Scholar
  68. 68.
    Silva M, et al. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood. 1996;88:1576–82.PubMedGoogle Scholar
  69. 69.
    Rojnuckarin P, Drachman JG. Kaushansky K. Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood. 1999;94:1273–82.PubMedGoogle Scholar
  70. 70.
    Hamelin V, Letourneux C, Romeo PH, Porteu F, Gaudry M. Thrombopoietin regulates IEX-1 gene expression through ERK-induced AML1 phosphorylation. Blood. 2006;107:3106–13.PubMedCrossRefGoogle Scholar
  71. 71.
    Geddis AE, Fox NE, Kaushansky K. Phosphatidylinositol 3-kinase is necessary but not sufficient for thrombopoietin-induced proliferation in engineered Mpl-bearing cell lines as well as in primary megakaryocytic progenitors. J Biol Chem. 2001;276:34473–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Nakao T, Geddis AE, Fox NE, Kaushansky K. PI3K/Akt/FOXO3a pathway contributes to thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27(Kip1). Cell Cycle. 2008;7:257–66.PubMedCrossRefGoogle Scholar
  73. 73.
    Tong W. Lodish HF. Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. J Exp Med. 2004;200:569–80.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Takizawa H, et al. Growth and maturation of megakaryocytes is regulated by Lnk/Sh2b3 adaptor protein through crosstalk between cytokine- and integrin-mediated signals. Exp Hematol. 2008;36:897–906.PubMedCrossRefGoogle Scholar
  75. 75.
    Kostyak JC, Naik MU, Naik UP. Calcium- and integrin-binding protein 1 regulates megakaryocyte ploidy, adhesion, and migration. Blood. 2012;119:838–46.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Bishton MJ, et al. Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia. Blood. 2011;117:3658–68.PubMedCrossRefGoogle Scholar
  77. 77.
    Wormald S, Hilton DJ. Inhibitors of cytokine signal transduction. J Biol Chem. 2004;279:821–4.PubMedCrossRefGoogle Scholar
  78. 78.
    Wang Q, Miyakawa Y, Fox N, Kaushansky K. Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. Blood. 2000;96:2093–9.PubMedGoogle Scholar
  79. 79.
    Lannutti BJ, Minear J, Blake N. Drachman JG. Increased megakaryocytopoiesis in Lyn-deficient mice. Oncogene. 2006;25:3316–24.PubMedCrossRefGoogle Scholar
  80. 80.
    Hitchcock IS, et al. Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function: studies using a megakaryocyte lineage specific FAK knockout. Blood. 2008;111:596–604.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Hitchcock IS, Chen MM, King JR, Kaushansky K. YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation. Blood. 2008;112:2222–31.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Collins BM, McCoy AJ, Kent HM, Evans PR, Owen DJ. Molecular architecture and functional model of the endocytic AP2 complex. Cell. 2002;109:523–35.PubMedCrossRefGoogle Scholar
  83. 83.
    Drachman JG, Kaushansky K. Dissecting the thrombopoietin receptor: functional elements of the Mpl cytoplasmic domain. Proc Natl Acad Sci U S A. 1997;94:2350–5.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Luoh SM, et al. Role of the distal half of the c-Mpl intracellular domain in control of platelet production by thrombopoietin in vivo. Mol Cell Biol. 2000;20:507–15.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Banno A, Ginsberg MH. Integrin activation. Biochem Soc Trans. 2008;36:229–34.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Kaushansky K. On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. Blood. 2005;105:4187–90.PubMedCrossRefGoogle Scholar
  87. 87.
    Theophile K, Hussein K, Kreipe H, Bock O. Expression profiling of apoptosis-related genes in megakaryocytes: BNIP3 is downregulated in primary myelofibrosis. Exp Hematol. 2008;36:1728–38.PubMedCrossRefGoogle Scholar
  88. 88.
    Chen E, et al. Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell. 2010;18:524–35.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Olthof SG, et al. Downregulation of signal transducer and activator of transcription 5 (STAT5) in CD34 + cells promotes megakaryocytic development, whereas activation of STAT5 drives erythropoiesis. Stem Cells. 2008;26:1732–42.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhang CC, et al. In silico protein interaction analysis using the global proteome machine database. J Proteome Res. 2011;10:656–68.PubMedCrossRefGoogle Scholar
  91. 91.
    Gieger C, et al. New gene functions in megakaryopoiesis and platelet formation. Nature. 2011;480:201–8.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Song WJ, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–75.PubMedCrossRefGoogle Scholar
  93. 93.
    Ichikawa M, et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med. 2004;10:299–304.PubMedCrossRefGoogle Scholar
  94. 94.
    Gilles L, et al. P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1. Blood. 2008;111:4081–91.PubMedCrossRefGoogle Scholar
  95. 95.
    Sitnicka E, et al. The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood. 1996;87:4998–5005.PubMedGoogle Scholar
  96. 96.
    Thorsteinsdottir U, Sauvageau G, Humphries RK. Enhanced in vivo regenerative potential of HOXB4-transduced hematopoietic stem cells with regulation of their pool size. Blood. 1999;94:2605–12.PubMedGoogle Scholar
  97. 97.
    Kirito K, Fox N, Kaushansky K. Thrombopoietin stimulates Hoxb4 expression: an explanation for the favorable effects of TPO on hematopoietic stem cells. Blood. 2003;102:3172–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Thorsteinsdottir U, et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood. 2002;99:121–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Kirito K, Fox N, Kaushansky K. Thrombopoietin induces HOXA9 nuclear transport in immature hematopoietic cells: potential mechanism by which the hormone favorably affects hematopoietic stem cells. Mol Cell Biol. 2004;24:6751–62.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Gerber HP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Kirito K, Kaushansky K. Thrombopoietin stimulates vascular endothelial cell growth factor (VEGF) production in hematopoietic stem cells. Cell Cycle. 2005;4:1729–31.PubMedCrossRefGoogle Scholar
  102. 102.
    Raslova H, et al. Megakaryocyte polyploidization is associated with a functional gene amplification. Blood. 2003;101:541–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Raslova H, et al. Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach. Blood. 2007;109:3225–34.PubMedCrossRefGoogle Scholar
  104. 104.
    Jung AS, Kaushansky A, Macbeath G, Kaushansky K. Tensin2 is a novel mediator in thrombopoietin (TPO)-induced cellular proliferation by promoting Akt signaling. Cell Cycle. 2011;10:1838–44.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Skogstrand K, et al. Simultaneous measurement of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xMAP technology. Clin Chem. 2005;51:1854–66.PubMedCrossRefGoogle Scholar
  106. 106.
    Wolf-Yadlin A, Sevecka M, MacBeath G. Dissecting protein function and signaling using protein microarrays. Curr Opin Chem Biol. 2009;13:398–405.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Basiji DA, Ortyn WE, Liang L, Venkatachalam V, Morrissey P. Cellular image analysis and imaging by flow cytometry. Clin Lab Med. 2007;27:653–70.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    George TC, et al. Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow. J Immunol Methods. 2006;311:117–29.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Malaria ProgramSeattle Biomedical Research InstituteSeattleUSA
  2. 2.Office of the Sr. Vice PresidentHealth SciencesStony BrookUSA

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