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JAK-STAT Signaling in Stem Cells

  • Rachel R. Stine
  • Erika L. MatunisEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 786)

Abstract

Adult stem cells are essential for the regeneration and repair of tissues in an organism. Signals from many different pathways converge to regulate stem cell maintenance and differentiation while preventing overproliferation. Although each population of adult stem cells is unique, common themes arise by comparing the regulation of various stem cell types in an organism or by comparing similar stem cell types across species. The JAK-STAT signaling pathway, identified nearly two decades ago, is now known to be involved in many biological processes including the regulation of stem cells. Studies in Drosophila first implicated JAK-STAT signaling in the control of stem cell maintenance in the male germline stem cell microenvironment, or niche; subsequently it has been shown play a role in other niches in both Drosophila and mammals. In this chapter, we will address the role of JAK-STAT signaling in stem cells in the germline, intestinal, hematopoietic and neuronal niches in Drosophila as well as the hematopoietic and neuronal niches in mammals. We will comment on how the study of JAK-STAT signaling in invertebrate systems has helped to advance our understanding of signaling in vertebrates. In addition to the role of JAK- STAT signaling in stem cell niche homeostasis, we will also discuss the diseases, including cancers, that can arise when this pathway is misregulated.

Keywords

JAK-STAT signaling Germ line stem cell Neural stem cell Intestinal stem cell Hematopoietic stem cell 

References

  1. 1.
    Ishihara K, Hirano T (2002) Molecular basis of the cell specificity of cytokine action. Biochim Biophys Acta (BBA) – Mol Cell Res 1592(3):281–296Google Scholar
  2. 2.
    Dearolf CR (1999) JAKs and STATs in invertebrate model organisms. Cell Mol Life Sci CMLS 55(12):1578–1584Google Scholar
  3. 3.
    Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117(Pt 8):1281–1283PubMedGoogle Scholar
  4. 4.
    Rakesh K, Agrawal DK (2005) Controlling cytokine signaling by constitutive inhibitors. Biochem Pharmacol 70(5):649–657PubMedGoogle Scholar
  5. 5.
    Ungureanu D, Vanhatupa S, Kotaja N, Yang J et al (2003) PIAS proteins promote SUMO-1 conjugation to STAT1. Blood 102(9):3311–3313PubMedGoogle Scholar
  6. 6.
    Ungureanu D, Vanhatupa S, Gronholm J, Palvimo JJ et al (2005) SUMO-1 conjugation selectively modulates STAT1-mediated gene responses. Blood 106(1):224–226PubMedGoogle Scholar
  7. 7.
    Gronholm J, Ungureanu D, Vanhatupa S, Ramet M et al (2010) Sumoylation of Drosophila transcription factor STAT92E. J Innate Immun 2(6):618–624PubMedGoogle Scholar
  8. 8.
    Shuai K, Stark GR, Kerr IM, Darnell JE Jr (1993) A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science 261(5129):1744–1746PubMedGoogle Scholar
  9. 9.
    Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R et al (1990) tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 5(9):1329–1336PubMedGoogle Scholar
  10. 10.
    Wilks AF, Harpur AG, Kurban RR, Ralph SJ et al (1991) Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol 11(4):2057–2065PubMedGoogle Scholar
  11. 11.
    Muller M, Briscoe J, Laxton C, Guschin D et al (1993) The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature 366(6451):129–135PubMedGoogle Scholar
  12. 12.
    Watling D, Guschin D, Muller M, Silvennoinen O et al (1993) Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature 366(6451):166–170PubMedGoogle Scholar
  13. 13.
    Shuai K, Ziemiecki A, Wilks AF, Harpur AG et al (1993) Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature 366(6455):580–583PubMedGoogle Scholar
  14. 14.
    Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063PubMedGoogle Scholar
  15. 15.
    Li WX (2008) Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol 18(11):545–551PubMedGoogle Scholar
  16. 16.
    Arbouzova NI, Zeidler MP (2006) JAK/STAT signalling in Drosophila: insights into conserved regulatory and cellular functions. Development 133(14):2605–2616PubMedGoogle Scholar
  17. 17.
    Binari R, Perrimon N (1994) Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila. Genes Dev 8(3):300–312PubMedGoogle Scholar
  18. 18.
    Hou XS, Melnick MB, Perrimon N (1996) Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. Cell 84(3):411–419PubMedGoogle Scholar
  19. 19.
    Harrison DA, McCoon PE, Binari R, Gilman M et al (1998) Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. Genes Dev 12(20):3252–3263PubMedGoogle Scholar
  20. 20.
    Agaisse H, Petersen UM, Boutros M, Mathey-Prevot B et al (2003) Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. Dev Cell 5(3):441–450PubMedGoogle Scholar
  21. 21.
    Brown S, Hu N, Hombría JC (2001) Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr Biol: CB 11(21):1700–1705PubMedGoogle Scholar
  22. 22.
    Makki R, Meister M, Pennetier D, Ubeda JM et al (2010) A short receptor downregulates JAK/STAT signalling to control the Drosophila cellular immune response. PLoS Biol 8(8):e1000441PubMedGoogle Scholar
  23. 23.
    Kallio J, Myllymaki H, Gronholm J, Armstrong M et al (2010) Eye transformer is a negative regulator of Drosophila JAK/STAT signaling. FASEB J 24(11):4467–4479PubMedGoogle Scholar
  24. 24.
    Kiger AA, Jones DL, Schulz C, Rogers MB et al (2001) Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science (New York) 294(5551):2542–2545Google Scholar
  25. 25.
    Tulina N, Matunis E (2001) Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science (New York) 294(5551):2546–2549Google Scholar
  26. 26.
    Gregory L, Came PJ, Brown S (2008) Stem cell regulation by JAK/STAT signaling in Drosophila. Semin Cell Dev Biol 19(4):407–413PubMedGoogle Scholar
  27. 27.
    Lin G, Xu N, Xi R (2010) Paracrine unpaired signaling through the JAK/STAT pathway controls self-renewal and lineage differentiation of drosophila intestinal stem cells. J Mol Cell Biol 2(1):37–49PubMedGoogle Scholar
  28. 28.
    Liu W, Singh SR, Hou SX (2010) JAK-STAT is restrained by Notch to control cell proliferation of the Drosophila intestinal stem cells. J Cell Biochem 109(5):992–999PubMedGoogle Scholar
  29. 29.
    Beebe K, Lee W-C, Micchelli CA (2010) JAK/STAT signaling coordinates stem cell proliferation and multilineage differentiation in the Drosophila intestinal stem cell lineage. Dev Biol 338(1):28–37PubMedGoogle Scholar
  30. 30.
    Jiang H, Patel PH, Kohlmaier A, Grenley MO et al (2009) Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137(7):1343–1355PubMedGoogle Scholar
  31. 31.
    Buchon N, Broderick NA, Chakrabarti S, Lemaitre B (2009) Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev 23(19):2333–2344PubMedGoogle Scholar
  32. 32.
    Krzemień J, Dubois L, Makki R, Meister M et al (2007) Control of blood cell homeostasis in Drosophila larvae by the posterior signalling centre. Nature 446(7133):325–328PubMedGoogle Scholar
  33. 33.
    Yasugi T, Umetsu D, Murakami S, Sato M et al (2008) Drosophila optic lobe neuroblasts triggered by a wave of proneural gene expression that is negatively regulated by JAK/STAT. Development 135(8):1471–1480PubMedGoogle Scholar
  34. 34.
    Wang W, Li Y, Zhou L, Yue H et al (2011) Role of JAK/STAT signaling in neuroepithelial stem cell maintenance and proliferation in the Drosophila optic lobe. Biochem Biophys Res Commun 410(4):714–720PubMedGoogle Scholar
  35. 35.
    Ngo KT, Wang J, Junker M, Kriz S et al (2010) Concomitant requirement for Notch and Jak/Stat signaling during neuro-epithelial differentiation in the Drosophila optic lobe. Dev Biol 346(2):284–295PubMedGoogle Scholar
  36. 36.
    Singh SR, Liu W, Hou SX (2007) The adult Drosophila Malpighian tubules are maintained by multipotent stem cells. Cell Stem Cell 1(2):191–203PubMedGoogle Scholar
  37. 37.
    Lopez-Onieva L, Fernandez-Minan A, Gonzalez-Reyes A (2008) Jak/Stat signalling in niche support cells regulates dpp transcription to control germline stem cell maintenance in the Drosophila ovary. Development 135(3):533–540PubMedGoogle Scholar
  38. 38.
    Hardy RW, Tokuyasu KT, Lindsley DL, Garavito M (1979) The germinal proliferation center in the testis of Drosophila melanogaster. J Ultrastruct Res 69(2):180–190PubMedGoogle Scholar
  39. 39.
    de Cuevas M, Matunis EL (2011) The stem cell niche: lessons from the Drosophila testis. Development 138(14):2861–2869PubMedGoogle Scholar
  40. 40.
    Sheng XR, Posenau T, Gumulak-Smith JJ, Matunis E et al (2009) Jak-STAT regulation of male germline stem cell establishment during Drosophila embryogenesis. Dev Biol 334(2):335–344PubMedGoogle Scholar
  41. 41.
    Issigonis M, Tulina N, de Cuevas M, Brawley C et al (2009) JAK-STAT signal inhibition regulates competition in the Drosophila testis stem cell niche. Science 326(5949):153–156PubMedGoogle Scholar
  42. 42.
    Singh SR, Zheng Z, Wang H, Oh S-W et al (2010) Competitiveness for the niche and mutual dependence of the germline and somatic stem cells in the Drosophila testis are regulated by the JAK/STAT signaling. J Cell Physiol 223(2):500–510PubMedGoogle Scholar
  43. 43.
    Leatherman JL, Dinardo S (2008) Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal. Cell Stem Cell 3(1):44–54PubMedGoogle Scholar
  44. 44.
    Leatherman JL, Dinardo S (2010) Germline self-renewal requires cyst stem cells and stat regulates niche adhesion in Drosophila testes. Nat Cell Biol 12(8):806–811PubMedGoogle Scholar
  45. 45.
    Flaherty MS, Salis P, Evans CJ, Ekas LA et al (2010) Chinmo is a functional effector of the JAK/STAT pathway that regulates eye development, tumor formation, and stem cell self-renewal in Drosophila. Dev Cell 18(4):556–568PubMedGoogle Scholar
  46. 46.
    Shivdasani AA, Ingham PW (2003) Regulation of stem cell maintenance and transit amplifying cell proliferation by tgf-beta signaling in Drosophila spermatogenesis. Curr Biol 13(23):2065–2072PubMedGoogle Scholar
  47. 47.
    Kawase E, Wong MD, Ding BC, Xie T (2004) Gbb/Bmp signaling is essential for maintaining germline stem cells and for repressing bam transcription in the Drosophila testis. Development 131(6):1365–1375PubMedGoogle Scholar
  48. 48.
    Song X, Wong MD, Kawase E, Xi R et al (2004) Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary. Development 131(6):1353–1364PubMedGoogle Scholar
  49. 49.
    Chen D, McKearin D (2003) Dpp signaling silences bam transcription directly to establish asymmetric divisions of germline stem cells. Curr Biol 13(20):1786–1791PubMedGoogle Scholar
  50. 50.
    Schulz C, Kiger AA, Tazuke SI, Yamashita YM et al (2004) A misexpression screen reveals effects of bag-of-marbles and TGF beta class signaling on the Drosophila male germ-line stem cell lineage. Genetics 167(2):707–723PubMedGoogle Scholar
  51. 51.
    Cherry CM, Matunis EL (2010) Epigenetic regulation of stem cell maintenance in the Drosophila testis via the nucleosome-remodeling factor NURF. Cell Stem Cell 6(6):557–567PubMedGoogle Scholar
  52. 52.
    Kwon SY, Xiao H, Glover BP, Tjian R et al (2008) The nucleosome remodeling factor (NURF) regulates genes involved in Drosophila innate immunity. Dev Biol 316(2):538–547PubMedGoogle Scholar
  53. 53.
    Classen AK, Bunker BD, Harvey KF, Vaccari T et al (2009) A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK-STAT signaling. Nat Genet 41(10):1150–1155PubMedGoogle Scholar
  54. 54.
    Su Y, Deng B, Xi R (2011) Polycomb group genes in stem cell self-renewal: a double-edged sword. Epigenetics 6(1):16–19PubMedGoogle Scholar
  55. 55.
    Voog J, D’Alterio C, Jones DL (2008) Multipotent somatic stem cells contribute to the stem cell niche in the Drosophila testis. Nature 454(7208):1132–1136PubMedGoogle Scholar
  56. 56.
    Brawley C, Matunis E (2004) Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science (New York) 304(5675):1331–1334Google Scholar
  57. 57.
    Sheng XR, Brawley CM, Matunis EL (2009) Dedifferentiating spermatogonia outcompete somatic stem cells for niche occupancy in the Drosophila testis. Cell Stem Cell 5(2):191–203PubMedGoogle Scholar
  58. 58.
    Nakagawa T, Sharma M, Nabeshima Y, Braun RE et al (2010) Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science 328(5974):62–67PubMedGoogle Scholar
  59. 59.
    Jiang H, Edgar BA (2011) Intestinal stem cells in the adult Drosophila midgut. Exp Cell Res 317(19):2780–2788PubMedGoogle Scholar
  60. 60.
    Hou SX (2010) Intestinal stem cell asymmetric division in the Drosophila posterior midgut. J Cell Physiol 224(3):581–584PubMedGoogle Scholar
  61. 61.
    Ohlstein B, Spradling A (2007) Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science 315(5814):988–992PubMedGoogle Scholar
  62. 62.
    Staley BK, Irvine KD (2010) Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr Biol: CB 20(17):1580–1587PubMedGoogle Scholar
  63. 63.
    Shaw RL, Kohlmaier A, Polesello C, Veelken C et al (2010) The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137(24):4147–4158PubMedGoogle Scholar
  64. 64.
    Ren F, Wang B, Yue T, Yun E-Y et al (2010) Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc Natl Acad Sci 107(49):21064–21069PubMedGoogle Scholar
  65. 65.
    Karpowicz P, Perez J, Perrimon N (2010) The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137(24):4135–4145PubMedGoogle Scholar
  66. 66.
    Crozatier M, Meister M (2007) Drosophila haematopoiesis. Cell Microbiol 9(5):1117–1126PubMedGoogle Scholar
  67. 67.
    Mandal L, Martinez-Agosto JA, Evans CJ, Hartenstein V et al (2007) A Hedgehog- and Antennapedia-dependent niche maintains Drosophila haematopoietic precursors. Nature 446(7133):320–324PubMedGoogle Scholar
  68. 68.
    Gao H, Wu X, Fossett N (2009) Upregulation of the Drosophila friend of GATA gene U-shaped by JAK/STAT signaling maintains lymph gland prohemocyte potency. Mol Cell Biol 29(22):6086–6096PubMedGoogle Scholar
  69. 69.
    Reifegerste R, Ma C, Moses K (1997) A polarity field is established early in the development of the Drosophila compound eye. Mech Dev 68(1–2):69–79PubMedGoogle Scholar
  70. 70.
    Forbes AJ, Lin H, Ingham PW, Spradling AC (1996) Hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. Development 122(4):1125–1135PubMedGoogle Scholar
  71. 71.
    Crozatier M, Vincent A (2011) Drosophila: a model for studying genetic and molecular aspects of ­haematopoiesis and associated leukaemias. Dis Models Mech 4(4):439–445Google Scholar
  72. 72.
    Boyle M, Wong C, Rocha M, Jones DL (2007) Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1(4):470–478PubMedGoogle Scholar
  73. 73.
    Krzemien J, Oyallon J, Crozatier M, Vincent A (2010) Hematopoietic progenitors and hemocyte lineages in the Drosophila lymph gland. Dev Biol 346(2):310–319PubMedGoogle Scholar
  74. 74.
    Stofanko M, Kwon SY, Badenhorst P (2010) Lineage tracing of lamellocytes demonstrates Drosophila macrophage plasticity. PLoS One 5(11):e14051PubMedGoogle Scholar
  75. 75.
    Egger B, Gold KS, Brand AH (2011) Regulating the balance between symmetric and asymmetric stem cell division in the developing brain. Fly 5(3):237–241PubMedGoogle Scholar
  76. 76.
    Egger B, Chell JM, Brand AH (2008) Insights into neural stem cell biology from flies. Philos Trans R Soc B: Biol Sci 363(1489):39–56Google Scholar
  77. 77.
    Wang W, Liu W, Wang Y, Zhou L et al (2011) Notch signaling regulates neuroepithelial stem cell maintenance and neuroblast formation in Drosophila optic lobe development. Dev Biol 350(2):414–428PubMedGoogle Scholar
  78. 78.
    Egger B, Gold KS, Brand AH (2010) Notch regulates the switch from symmetric to asymmetric neural stem cell division in the Drosophila optic lobe. Development 137(18):2981–2987PubMedGoogle Scholar
  79. 79.
    Yasugi T, Sugie A, Umetsu D, Tabata T (2010) Coordinated sequential action of EGFR and Notch signaling pathways regulates proneural wave progression in the Drosophila optic lobe. Development 137(19):3193–3203PubMedGoogle Scholar
  80. 80.
    Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC et al (2002) “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298(5593):597–600PubMedGoogle Scholar
  81. 81.
    Wang LD, Wagers AJ (2011) Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat Rev Mol Cell Biol 12(10):643–655PubMedGoogle Scholar
  82. 82.
    Miller FD, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54(3):357–369PubMedGoogle Scholar
  83. 83.
    Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4(1–2):7–25PubMedGoogle Scholar
  84. 84.
    Trumpp A, Essers M, Wilson A (2010) Awakening dormant haematopoietic stem cells. Nat Rev Immunol 10(3):201–209PubMedGoogle Scholar
  85. 85.
    Seita J, Weissman IL (2010) Hematopoietic stem cell: self‐renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med 2(6):640–653PubMedGoogle Scholar
  86. 86.
    Snow JW, Abraham N, Ma MC, Abbey NW et al (2002) STAT5 promotes multilineage hematolymphoid development in vivo through effects on early hematopoietic progenitor cells. Blood 99(1):95–101PubMedGoogle Scholar
  87. 87.
    Bradley HL, Couldrey C, Bunting KD (2004) Hematopoietic-repopulating defects from STAT5-deficient bone marrow are not fully accounted for by loss of thrombopoietin responsiveness. Blood 103(8):2965–2972PubMedGoogle Scholar
  88. 88.
    Ema H, Sudo K, Seita J, Matsubara A et al (2005) Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. Dev Cell 8(6):907–914PubMedGoogle Scholar
  89. 89.
    Seita J, Ema H, Ooehara J, Yamazaki S et al (2007) Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction. Proc Natl Acad Sci USA 104(7):2349–2354PubMedGoogle Scholar
  90. 90.
    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(8):2832–2844PubMedGoogle Scholar
  91. 91.
    Kato Y, Iwama A, Tadokoro Y, Shimoda K et al (2005) Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis. J Exp Med 202(1):169–179PubMedGoogle Scholar
  92. 92.
    Wang Z, Li G, Tse W, Bunting KD (2009) Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement. Blood 113(20):4856–4865PubMedGoogle Scholar
  93. 93.
    Chung Y-J, Park B-B, Kang Y-J, Kim T-M et al (2006) Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration. Blood 108(4):1208–1215PubMedGoogle Scholar
  94. 94.
    Oh IH, Eaves CJ (2002) Overexpression of a dominant negative form of STAT3 selectively impairs hematopoietic stem cell activity. Oncogene 21(31):4778–4787PubMedGoogle Scholar
  95. 95.
    Coffer PJ, Koenderman L, de Groot RP (2000) The role of STATs in myeloid differentiation and leukemia. Oncogene 19(21):2511–2522PubMedGoogle Scholar
  96. 96.
    Dorsch M, Danial NN, Rothman PB, Goff SP (1999) A thrombopoietin receptor mutant deficient in Jak-STAT activation mediates proliferation but not differentiation in UT-7 cells. Blood 94(8):2676–2685PubMedGoogle Scholar
  97. 97.
    Arcasoy MO, Jiang X (2005) Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor. Br J Haematol 130(1):121–129PubMedGoogle Scholar
  98. 98.
    Essers MAG, Offner S, Blanco-Bose WE, Waibler Z et al (2009) IFN[agr] activates dormant haematopoietic stem cells in vivo. Nature 458(7240):904–908PubMedGoogle Scholar
  99. 99.
    Baldridge MT, King KY, Goodell MA (2011) Inflammatory signals regulate hematopoietic stem cells. Trends Immunol 32(2):57–65PubMedGoogle Scholar
  100. 100.
    Malatesta P, Appolloni I, Calzolari F (2008) Radial glia and neural stem cells. Cell Tissue Res 331(1):165–178PubMedGoogle Scholar
  101. 101.
    Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184PubMedGoogle Scholar
  102. 102.
    Bonni A, Sun Y, Nadal-Vicens M, Bhatt A et al (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278(5337):477–483PubMedGoogle Scholar
  103. 103.
    Barnabé-Heider F, Wasylnka JA, Fernandes KJL, Porsche C et al (2005) Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 48(2):253–265PubMedGoogle Scholar
  104. 104.
    He F, Ge W, Martinowich K, Becker-Catania S et al (2005) A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 8(5):616–625PubMedGoogle Scholar
  105. 105.
    Nakashima K, Yanagisawa M, Arakawa H, Kimura N et al (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science (New York) 284(5413):479–482Google Scholar
  106. 106.
    Fukuda S, Abematsu M, Mori H, Yanagisawa M et al (2007) Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells. Mol Cell Biol 27(13):4931–4937PubMedGoogle Scholar
  107. 107.
    Viti J, Feathers A, Phillips J, Lillien L (2003) Epidermal growth factor receptors control competence to interpret leukemia inhibitory factor as an astrocyte inducer in developing cortex. J Neurosci Off J Soc Neurosci 23(8):3385–3393Google Scholar
  108. 108.
    Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M et al (2004) Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol 6(6):547–554PubMedGoogle Scholar
  109. 109.
    Yeung TM, Chia LA, Kosinski CM, Kuo CJ (2011) Regulation of self-renewal and differentiation by the intestinal stem cell niche. Cell Mol Life Sci 68(15):2513–2523PubMedGoogle Scholar
  110. 110.
    Fan G, Martinowich K, Chin MH, He F et al (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132(15):3345–3356PubMedGoogle Scholar
  111. 111.
    Kohyama J, Kojima T, Takatsuka E, Yamashita T et al (2008) Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain. Proc Natl Acad Sci U S A 105(46):18012–18017PubMedGoogle Scholar
  112. 112.
    Irmady K, Zechel S, Unsicker K (2011) Fibroblast growth factor 2 regulates astrocyte differentiation in a region-specific manner in the hindbrain. Glia 59(5):708–719PubMedGoogle Scholar
  113. 113.
    Harrison DA, Binari R, Nahreini TS, Gilman M et al (1995) Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J 14(12):2857–2865PubMedGoogle Scholar
  114. 114.
    Betz A, Lampen N, Martinek S, Young MW et al (2001) A Drosophila PIAS homologue negatively regulates stat92E. Proc Natl Acad Sci USA 98(17):9563–9568PubMedGoogle Scholar
  115. 115.
    Atkinson GP, Nozell SE, Benveniste ET (2010) NF-kappaB and STAT3 signaling in glioma: targets for future therapies. Expert Rev Neurother 10(4):575–586PubMedGoogle Scholar
  116. 116.
    Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15(9):1010–1012PubMedGoogle Scholar
  117. 117.
    Borovski T, De Sousa E, Melo F, Vermeulen L, Medema JP (2011) Cancer stem cell niche: the place to be. Cancer Res 71(3):634–639PubMedGoogle Scholar
  118. 118.
    Lapidot T, Sirard C, Vormoor J, Murdoch B et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367(6464):645–648PubMedGoogle Scholar
  119. 119.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci 100(7):3983–3988PubMedGoogle Scholar
  120. 120.
    Galli R, Binda E, Orfanelli U, Cipelletti B et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021PubMedGoogle Scholar
  121. 121.
    Schatton T, Murphy GF, Frank NY, Yamaura K et al (2008) Identification of cells initiating human melanomas. Nature 451(7176):345–349PubMedGoogle Scholar
  122. 122.
    Zhou J, Wulfkuhle J, Zhang H, Gu P et al (2007) Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA 104(41):16158–16163PubMedGoogle Scholar
  123. 123.
    Birnie R, Bryce SD, Roome C, Dussupt V et al (2008) Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions. Genome Biol 9(5):R83–R83PubMedGoogle Scholar
  124. 124.
    Liu X, He Z, Li C-H, Huang G et al (2011) Correlation analysis of JAK-STAT pathway components on prognosis of patients with prostate cancer. Pathol Oncol Res 18:17–23Google Scholar
  125. 125.
    Barton BE, Karras JG, Murphy TF, Barton A et al (2004) Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther 3(1):11–20PubMedGoogle Scholar
  126. 126.
    Natsume A, Kinjo S, Yuki K, Kato T et al (2011) Glioma-initiating cells and molecular pathology: implications for therapy. Brain Tumor Pathol 28(1):1–12PubMedGoogle Scholar
  127. 127.
    Singh SK, Hawkins C, Clarke ID, Squire JA et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401PubMedGoogle Scholar
  128. 128.
    Lee J, Son MJ, Woolard K, Donin NM et al (2008) Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13(1):69–80PubMedGoogle Scholar
  129. 129.
    Peñuelas S, Anido J, Prieto-Sánchez RM, Folch G et al (2009) TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15(4):315–327PubMedGoogle Scholar
  130. 130.
    Sherry MM, Reeves A, Wu JK, Cochran BH (2009) STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27(10):2383–2392PubMedGoogle Scholar
  131. 131.
    de la Iglesia N, Konopka G, Lim KL, Nutt CL et al (2008) Deregulation of a STAT3-interleukin 8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness. J Neurosci 28(23):5870–5878PubMedGoogle Scholar
  132. 132.
    Tu Y, Zhong Y, Fu J, Cao Y et al (2010) Activation of JAK/STAT signal pathway predicts poor prognosis of patients with gliomas. Med Oncol 28(1):15–23PubMedGoogle Scholar
  133. 133.
    Testa U (2011) Leukemia stem cells. Ann Hematol 90(3):245–271PubMedGoogle Scholar
  134. 134.
    Heuser M, Sly LM, Argiropoulos B, Kuchenbauer F et al (2009) Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal. Blood 114(19):3983–3993PubMedGoogle Scholar
  135. 135.
    Benekli M, Xia Z, Donohue KA, Ford LA et al (2002) Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood 99(1):252–257PubMedGoogle Scholar
  136. 136.
    Hart S, Goh KC, Novotny-Diermayr V, Hu CY et al (2011) SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 25(11):1751–1759PubMedGoogle Scholar
  137. 137.
    Scuto A, Krejci P, Popplewell L, Wu J et al (2011) The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia 25(3):538–550PubMedGoogle Scholar
  138. 138.
    Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S (2011) Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 10(2):127–140PubMedGoogle Scholar
  139. 139.
    Kralovics R, Passamonti F, Buser AS, Teo S-S et al (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352(17):1779–1790PubMedGoogle Scholar
  140. 140.
    Dameshek W (1951) Some speculations on the myeloproliferative syndromes. Blood 6(4):372–375PubMedGoogle Scholar
  141. 141.
    Adamson JW, Fialkow PJ, Murphy S, Prchal JF et al (1976) Polycythemia vera: stem-cell and probable clonal origin of the disease. N Engl J Med 295(17):913–916PubMedGoogle Scholar
  142. 142.
    el-Kassar N, Hetet G, Brière J, Grandchamp B (1997) Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets. Blood 89(1):128–134PubMedGoogle Scholar
  143. 143.
    Spivak JL (2004) The chronic myeloproliferative disorders: clonality and clinical heterogeneity. Semin Hematol 41(2 Suppl 3):1–5PubMedGoogle Scholar
  144. 144.
    Oh ST, Gotlib J (2010) JAK2 V617F and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms. Expert Rev Hematol 3(3):323–337PubMedGoogle Scholar
  145. 145.
    Röder S, Steimle C, Meinhardt G, Pahl HL (2001) STAT3 is constitutively active in some patients with polycythemia rubra vera. Exp Hematol 29(6):694–702PubMedGoogle Scholar
  146. 146.
    Kralovics R, Guan Y, Prchal JT (2002) Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol 30(3):229–236PubMedGoogle Scholar
  147. 147.
    James C, Ugo V, Le Couédic J-P, Staerk J et al (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434(7037):1144–1148PubMedGoogle Scholar
  148. 148.
    Levine RL, Wadleigh M, Cools J, Ebert BL et al (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7(4):387–397PubMedGoogle Scholar
  149. 149.
    Ugo V, Marzac C, Teyssandier I, Larbret F et al (2004) Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol 32(2):179–187PubMedGoogle Scholar
  150. 150.
    Passamonti F, Maffioli M, Caramazza D, Cazzola M (2011) Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget 2(6):485–490PubMedGoogle Scholar
  151. 151.
    Quintás-Cardama A, Verstovsek S (2011) New JAK2 inhibitors for myeloproliferative neoplasms. Expert Opin Investig Drugs 20(7):961–972PubMedGoogle Scholar
  152. 152.
    Mathur A, Mo J-R, Kraus M, O’Hare E et al (2009) An inhibitor of Janus kinase 2 prevents polycythemia in mice. Biochem Pharmacol 78(4):382–389PubMedGoogle Scholar
  153. 153.
    Murphy K, Carvajal L, Medico L, Pepling M (2005) Expression of Stat3 in germ cells of developing and adult mouse ovaries and testes. Gene Expr Patterns 5(4):475–482PubMedGoogle Scholar
  154. 154.
    Oatley JM, Kaucher AV, Avarbock MR, Brinster RL (2010) Regulation of mouse spermatogonial stem cell differentiation by STAT3 signaling. Biol ReprodGoogle Scholar
  155. 155.
    Wu J, Zhang Y, Tian GG, Zou K et al (2008) Short-type PB-cadherin promotes self-renewal of spermatogonial stem cells via multiple signaling pathways. Cell Signal 20(6):1052–1060PubMedGoogle Scholar
  156. 156.
    Sun J (2010) Enteric bacteria and cancer stem cells. Cancers 3(1):285–297PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Cell BiologyJohns Hopkins University School of MedicineBaltimoreUSA

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