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Miscreant myeloproliferative disorder stem cells

Leukemia volume 22, pages 2011–2019 (2008)Cite this article

Abstract

Myeloproliferative disorders (MPDs), typified by robust marrow and extramedullary hematopoiesis, have a propensity to progress to acute leukemia. Although the hematopoietic stem cell (HSC) origin of MPDs was suggested over 30 years ago, only recently the HSC-specific effects of MPD molecular mutations have been investigated. The pivotal role of BCR-ABL in chronic myeloid leukemia (CML) development provided the rationale for targeted therapy, which greatly reduced mortality rates. However, BCR-ABL inhibitor-resistant CML HSCs persist that may be a reservoir for relapse. This has provided the impetus for investigating molecular mechanisms governing the production of recalcitrant HSC. Comparatively little was known about the molecular events driving BCR-ABL-negative MPDs until seminal studies revealed that a large proportion of MPD patients harbor a JAK2-activating point mutation, JAK2V617F. Although JAK2 activation appears to be central to BCR-ABL-negative MPD pathogenesis, its effects may be cell type and context specific. Recent evidence suggests that acquired mutations misdirect differentiation and survival of the MPD-initiating stem cell resulting in the production of aberrant self-renewing progenitors that subvert the microenvironment leading to leukemia stem cell generation and leukemic transformation. Thus, combined therapies targeting aberrant molecular pathways may be required to redirect miscreant MPD stem cells.

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References

  1. Dameshek W . Some speculations on the myeloproliferative syndromes. Blood 1951; 6: 372–375.

    CAS  PubMed  Google Scholar 

  2. Adamson JW, Fialkow PJ, Murphy S, Prchal JF, Steinmann L . Polycythemia vera: stem-cell and probable clonal origin of the disease. N Engl J Med 1976; 295: 913–916.

    CAS  PubMed  Google Scholar 

  3. Murphy S . Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood 1981; 58: 916–919.

    PubMed  Google Scholar 

  4. Jacobson RJ, Salo A, Fialkow PJ . Agnogenic myeloid metaplasia: a clonal proliferation of hematopoietic stem cells with secondary myelofibrosis. Blood 1978; 51: 189–194.

    CAS  PubMed  Google Scholar 

  5. Fialkow PJ, Jacobson RJ, Papayannopoulou T . Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med 1977; 63: 125–130.

    CAS  PubMed  Google Scholar 

  6. Gilliland DG, Blanchard KL, Levy J, Perrin S, Bunn HF . Clonality in myeloproliferative disorders: analysis by means of the polymerase chain reaction. Proc Natl Acad Sci USA 1991; 88: 6848–6852.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nowell PC, Hungerford DA . Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 1960; 25: 85–109.

    CAS  PubMed  Google Scholar 

  8. Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G . Structural organization of the bcr gene and its role in the Ph′ translocation. Nature 1985; 315: 758–761.

    CAS  PubMed  Google Scholar 

  9. Konopka JB, Watanabe SM, Singer JW, Collins SJ, Witte ON . Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. Proc Natl Acad Sci USA 1985; 82: 1810–1814.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Westbrook CA, Rubin CM, Carrino JJ, Le Beau MM, Bernards A, Rowley JD . Long-range mapping of the Philadelphia chromosome by pulsed-field gel electrophoresis. Blood 1988; 71: 697–702.

    CAS  PubMed  Google Scholar 

  11. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

    Article  CAS  PubMed  Google Scholar 

  12. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J . Acute leukaemia in bcr/abl transgenic mice. Nature 1990; 344: 251–253.

    CAS  PubMed  Google Scholar 

  13. Daley GQ, Van Etten RA, Baltimore D . Blast crisis in a murine model of chronic myelogenous leukemia. Proc Natl Acad Sci USA 1991; 88: 11335–11338.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 1998; 92: 3780–3792.

    CAS  PubMed  Google Scholar 

  15. Heisterkamp N, Jenster G, Kioussis D, Pattengale PK, Groffen J . Human bcr-abl gene has a lethal effect on embryogenesis. Transgenic Res 1991; 1: 45–53.

    CAS  PubMed  Google Scholar 

  16. Deininger MW, Goldman JM, Melo JV . The molecular biology of chronic myeloid leukemia. Blood 2000; 96: 3343–3356.

    CAS  PubMed  Google Scholar 

  17. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037.

    CAS  PubMed  Google Scholar 

  18. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    Article  CAS  PubMed  Google Scholar 

  19. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.

    CAS  PubMed  Google Scholar 

  20. Holyoake T, Jiang X, Eaves C, Eaves A . Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 1999; 94: 2056–2064.

    CAS  PubMed  Google Scholar 

  21. Jørgensen HG, Copland M, Allan EK, Jiang X, Eaves A, Eaves C et al. Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 2006; 12: 626–633.

    PubMed  Google Scholar 

  22. Geron I, Abrahamsson AE, Barroga CF, Kavalerchik E, Gotlib J, Hood JD et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell 2008; 13: 321–330.

    CAS  PubMed  Google Scholar 

  23. Jamieson CH, Gotlib J, Durocher JA, Chao MP, Mariappan MR, Lay M et al. The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc Natl Acad Sci USA 2006; 103: 6224–6229.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.

    CAS  PubMed  Google Scholar 

  25. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

    CAS  PubMed  Google Scholar 

  26. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 2007; 356: 217–226.

    CAS  PubMed  Google Scholar 

  28. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.

    Article  CAS  PubMed  Google Scholar 

  29. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444: 756–760.

    CAS  PubMed  Google Scholar 

  30. O’Brien CA, Pollett A, Gallinger S, Dick JE . A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106–110.

    PubMed  Google Scholar 

  31. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007; 104: 10158–10163.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V et al. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67: 1030–1037.

    CAS  PubMed  Google Scholar 

  33. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M et al. Identification of cells initiating human melanomas. Nature 2008; 451: 345–349.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sirard C, Lapidot T, Vormoor J, Cashman JD, Doedens M, Murdoch B et al. Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis. Blood 1996; 87: 1539–1548.

    CAS  PubMed  Google Scholar 

  35. Wang JC, Lapidot T, Cashman JD, Doedens M, Addy L, Sutherland DR et al. High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 1998; 91: 2406–2414.

    CAS  PubMed  Google Scholar 

  36. Passegue E, Wagner EF, Weissman IL . JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 2004; 119: 431–443.

    CAS  PubMed  Google Scholar 

  37. Mohty M, Szydlo RM, Yong AS, Apperley JF, Goldman JM, Melo JV . The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood 2007; 110: 380–383.

    CAS  PubMed  Google Scholar 

  38. Cao R, Tsukada Y, Zhang Y . Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell 2005; 20: 845–854.

    CAS  PubMed  Google Scholar 

  39. Strathdee G, Holyoake TL, Sim A, Parker A, Oscier DG, Melo JV et al. Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis. Clin Cancer Res 2007; 13: 5048–5055.

    CAS  PubMed  Google Scholar 

  40. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 2794–2799.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Gambacorti-Passerini C, le Coutre P, Mologni L, Fanelli M, Bertazzoli C, Marchesi E et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 1997; 23: 380–394.

    CAS  PubMed  Google Scholar 

  42. Adams JM, Cory S . The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007; 26: 1324–1337.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Franke TF, Kaplan DR, Cantley LC . PI3K: downstream AKT blocks apoptosis. Cell 1997; 88: 435–437.

    CAS  PubMed  Google Scholar 

  44. de Groot RP, Raaijmakers JA, Lammers JW, Koenderman L . STAT5-dependent cyclinD1 and Bcl-xL expression in Bcr-Abl-transformed cells. Mol Cell Biol Res Commun 2000; 3: 299–305.

    CAS  PubMed  Google Scholar 

  45. Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I et al. Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL. J Exp Med 2000; 191: 977–984.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Gesbert F, Griffin JD . Bcr/Abl activates transcription of the Bcl-X gene through STAT5. Blood 2000; 96: 2269–2276.

    CAS  PubMed  Google Scholar 

  47. Sanchez-Garcia I, Grutz G . Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. Proc Natl Acad Sci USA 1995; 92: 5287–5291.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS et al. BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. Blood 1995; 86: 1148–1158.

    CAS  PubMed  Google Scholar 

  49. Albrecht T, Schwab R, Henkes M, Peschel C, Huber C, Aulitzky WE . Primary proliferating immature myeloid cells from CML patients are not resistant to induction of apoptosis by DNA damage and growth factor withdrawal. Br J Haematol 1996; 95: 501–507.

    CAS  PubMed  Google Scholar 

  50. Amos TA, Lewis JL, Grand FH, Gooding RP, Goldman JM, Gordon MY . Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids. Br J Haematol 1995; 91: 387–393.

    CAS  PubMed  Google Scholar 

  51. Cortez D, Kadlec L, Pendergast AM . Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis. Mol Cell Biol 1995; 15: 5531–5541.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Nishii K, Kabarowski JH, Gibbons DL, Griffiths SD, Titley I, Wiedemann LM et al. BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block. Oncogene 1996; 13: 2225–2234.

    CAS  PubMed  Google Scholar 

  53. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ . Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 1994; 83: 2038–2044.

    CAS  PubMed  Google Scholar 

  54. McGahon A, Bissonnette R, Schmitt M, Cotter KM, Green DR, Cotter TG . BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood 1994; 83: 1179–1187.

    CAS  PubMed  Google Scholar 

  55. Gaiger A, Henn T, Hörth E, Geissler K, Mitterbauer G, Maier-Dobersberger T et al. Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. Blood 1995; 86: 2371–2378.

    CAS  PubMed  Google Scholar 

  56. Jaiswal S, Traver D, Miyamoto T, Akashi K, Lagasse E, Weissman IL . Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias. Proc Natl Acad Sci USA 2003; 100: 10002–10007.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhao Y, Altman BJ, Coloff JL, Herman CE, Jacobs SR, Wieman HL et al. Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Mol Cell Biol 2007; 27: 4328–4339.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003; 17: 590–603.

    CAS  PubMed  Google Scholar 

  59. Hayden MS, Ghosh S . Shared principles in NF-kappaB signaling. Cell 2008; 132: 344–362.

    CAS  PubMed  Google Scholar 

  60. Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin Jr AS . A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev 1998; 12: 968–981.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kirchner D, Duyster J, Ottmann O, Schmid RM, Bergmann L, Munzert G . Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation. Exp Hematol 2003; 31: 504–511.

    CAS  PubMed  Google Scholar 

  62. Vejda S, Piwocka K, McKenna SL, Cotter TG . Autocrine secretion of osteopontin results in degradation of I kappa B in Bcr-Abl-expressing cells. Br J Haematol 2005; 128: 711–721.

    CAS  PubMed  Google Scholar 

  63. Flamant S, Kortulewski T, Dugray A, Bonnet ML, Guillier M, Guilhot F et al. Osteopontin is upregulated by BCR-ABL. Biochem Biophys Res Commun 2005; 333: 1378–1384.

    CAS  PubMed  Google Scholar 

  64. Hickey FB, England K, Cotter TG . Bcr-Abl regulates osteopontin transcription via Ras, PI-3K, aPKC, Raf-1, and MEK. J Leukoc Biol 2005; 78: 289–300.

    CAS  PubMed  Google Scholar 

  65. Mayack SR, Wagers AJ . Osteolineage niche cells initiate hematopoietic stem cell mobilization. Blood 2008; 112: 519–531.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jones DL, Wagers AJ . No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol 2008; 9: 11–21.

    CAS  PubMed  Google Scholar 

  67. Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T, Grünewald E et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med 2005; 201: 1781–1791.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ, Denhardt DT et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 2005; 106: 1232–1239.

    CAS  PubMed  Google Scholar 

  69. Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R . Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci USA 2003; 100: 6523–6528.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Komatsu N, Watanabe T, Uchida M, Mori M, Kirito K, Kikuchi S et al. A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells. J Biol Chem 2003; 278: 6411–6419.

    CAS  PubMed  Google Scholar 

  71. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.

    CAS  PubMed  Google Scholar 

  72. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

    CAS  PubMed  Google Scholar 

  73. James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

    CAS  PubMed  Google Scholar 

  74. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia. Cancer Cell 2005; 7: 387–397.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.

    CAS  PubMed  Google Scholar 

  77. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459–468.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007; 21: 1658–1668.

    CAS  PubMed  Google Scholar 

  79. Kaushansky K . On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. Blood 2005; 105: 4187–4190.

    CAS  PubMed  Google Scholar 

  80. Kaushansky K . Lineage-specific hematopoietic growth factors. N Engl J Med 2006; 354: 2034–2045.

    CAS  PubMed  Google Scholar 

  81. Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A . TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 2008; 22: 1790–1792.

    CAS  PubMed  Google Scholar 

  82. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008; 13: 311–320.

    CAS  PubMed  Google Scholar 

  83. Barroga CF, Pham H, Kaushansky K . Thrombopoietin regulates c-myb expression by regulating micro RNA 150 expression. Exp Hematol, in press, published online 24 September 2008.

  84. Bruchova H, Merkerova M, Prchal JT . Aberrant expression of microRNA in polycythemia vera. Haematologica 2008; 93: 1009–1016.

    CAS  PubMed  Google Scholar 

  85. Bruchova H, Yoon D, Agarwal AM, Mendell J, Prchal JT . Regulated expression of microRNAs in normal and polycythemia vera erythropoiesis. Exp Hematol 2007; 35: 1657–1667.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Wernig G, Gonneville JR, Crowley BJ, Rodrigues MS, Reddy MM, Hudon HE et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood 2008; 111: 3751–3759.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Dupont S, Massé A, James C, Teyssandier I, Lécluse Y, Larbret F et al. The JAK2 V617VF mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood 2007; 110: 1013–1021.

    CAS  PubMed  Google Scholar 

  88. Van Pelt K, Nollet F, Selleslag D, Knoops L, Constantinescu SN, Criel A et al. The JAK2 mutation can occur in a stem cell that has no proliferative advantage: a case of human allogeneic transplantation. Blood 2008; 112: 921–922.

    CAS  PubMed  Google Scholar 

  89. James C, Mazurier F, Dupont S, Chaligne R, Lamrissi-Garcia I, Tulliez M et al. The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity. Blood 2008; 112: 2429–2438.

    CAS  PubMed  Google Scholar 

  90. Kralovics R, Guan Y, Prchal JT . Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol 2002; 30: 229–236.

    CAS  PubMed  Google Scholar 

  91. Ishii T, Bruno E, Hoffman R, Xu M . Involvement of various hematopoietic-cell lineages by the JAKV617F mutation in polycythemia vera. Blood 2006; 108: 3128–3134.

    CAS  PubMed  Google Scholar 

  92. Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E et al. Leukemic blasts in transformed JAK2V617F positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007; 110: 375–379.

    CAS  PubMed  Google Scholar 

  93. Tefferi A, Gilliland DG . Oncogenes in myeloproliferative disorders. Cell Cycle 2007; 6: 550–566.

    CAS  PubMed  Google Scholar 

  94. Wilks AF . Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc Natl Acad Sci USA 1989; 86: 1603–1607.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Lu X, Huang LJ, Lodish HF . Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. J Biol Chem 2008; 283: 5258–5266.

    CAS  PubMed  Google Scholar 

  96. Tong W, Ibarra YM, Lodish HF . Signals emanating from the membrane proximal region of the thrombopoietin receptor (mpl) support hematopoietic stem cell self-renewal. Exp Hematol 2007; 35: 1447–1455.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Grebien F, Kerenyi MA, Kovacic B, Kolbe T, Becker V, Dolznig H et al. Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. Blood 2008; 111: 4511–4522.

    CAS  PubMed  Google Scholar 

  98. Garçon L, Rivat C, James C, Lacout C, Camara-Clayette V, Ugo V et al. Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells. Blood 2006; 108: 1551–1554.

    PubMed  Google Scholar 

  99. Prade-Houdellier N, Frébet E, Demur C, Gautier EF, Delhommeau F, Bennaceur-Griscelli AL et al. Human telomerase is regulated by erythropoietin and transforming growth factor-beta in human erythroid progenitor cells. Leukemia 2007; 21: 2304–2310.

    CAS  PubMed  Google Scholar 

  100. Wang JC, Hemavathy K, Charles W, Zhang H, Dua PK, Novetsky AD et al. Osteosclerosis in idiopathic myelofibrosis is related to overproduction of osteoprotegerin (OPG). Exp Hematol 2004; 32: 905–910.

    CAS  PubMed  Google Scholar 

  101. Vardiman JW, Brunning RD, Harris NL . WHO histological classification of chronic myeloproliferative diseases. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumors: Tumours of the Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer (IARC) Press: Lyon, France, 2001, pp 17–44.

    Google Scholar 

  102. Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007; 110: 1092–1097.

    CAS  PubMed  Google Scholar 

  103. Mesa RA, Verstovsek S, Cervantes F, Barosi G, Reilly JT, Dupriez B et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Leuk Res 2007; 31: 737–740.

    PubMed  Google Scholar 

  104. Landolfi R, Di Gennaro L, Barbui T, De Stefano V, Finazzi G, Marfisi R et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 2007; 109: 2446–2452.

    CAS  PubMed  Google Scholar 

  105. Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007; 110: 840–846.

    CAS  PubMed  Google Scholar 

  106. Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996; 88: 1013–1018.

    CAS  PubMed  Google Scholar 

  107. Dingli D, Schwager SM, Mesa RA, Li CY, Tefferi A . Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system. Cancer 2006; 106: 623–630.

    PubMed  Google Scholar 

  108. Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114–124.

    CAS  PubMed  Google Scholar 

  109. Di Nisio M, Barbui T, Di Gennaro L, Borrelli G, Finazzi G, Landolfi R et al. The haematocrit and platelet target in polycythemia vera. Br J Haematol 2007; 136: 249–259.

    PubMed  Google Scholar 

  110. Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 332: 1132–1136.

    CAS  PubMed  Google Scholar 

  111. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 33–45.

    CAS  PubMed  Google Scholar 

  112. Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli C et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005; 105: 2664–2670.

    CAS  PubMed  Google Scholar 

  113. Kiladjian JJ, Cassinat B, Turlure P, Cambier N, Roussel M, Bellucci S et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood 2006; 108: 2037–2040.

    CAS  PubMed  Google Scholar 

  114. Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Torrebadell M, Montserrat E . Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol 2004; 127: 399–403.

    CAS  PubMed  Google Scholar 

  115. Cervantes F, Hernandez-Boluda JC, Alvarez A, Nadal E, Montserrat E . Danazol treatment of idiopathic myelofibrosis with severe anemia. Haematologica 2000; 85: 595–599.

    CAS  PubMed  Google Scholar 

  116. Lofvenberg E, Wahlin A, Roos G, Ost A . Reversal of myelofibrosis by hydroxyurea. Eur J Haematol 1990; 44: 33–38.

    CAS  PubMed  Google Scholar 

  117. Faoro LN, Tefferi A, Mesa RA . Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia. Eur J Haematol 2005; 74: 117–120.

    CAS  PubMed  Google Scholar 

  118. Deeg HJ, Gooley TA, Flowers ME, Sale GE, Slattery JT, Anasetti C et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102: 3912–3918.

    CAS  PubMed  Google Scholar 

  119. Rondelli D, Barosi G, Bacigalupo A, Prchal JT, Popat U, Alessandrino EP et al. Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in intermediate or high risk patients with myelofibrosis with myeloid metaplasia. Blood 2005; 105: 4115–4119.

    CAS  PubMed  Google Scholar 

  120. Barosi G, Grossi A, Comotti B, Musto P, Gamba G, Marchetti M . Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 2001; 114: 78–83.

    CAS  PubMed  Google Scholar 

  121. Mesa RA, Steensma DP, Pardanani A, Li CY, Elliott M, Kaufmann SH et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003; 101: 2534–2541.

    CAS  PubMed  Google Scholar 

  122. Tefferi A, Cortes J, Verstovsek S, Mesa RA, Thomas D, Lasho TL et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006; 108: 1158–1164.

    CAS  PubMed  Google Scholar 

  123. Tefferi A, Lasho TL, Mesa RA, Pardanani A, Ketterling RP, Hanson CA . Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia 2007; 21: 1827–1828.

    CAS  PubMed  Google Scholar 

  124. Silver RT . Imatinib mesylate (Gleevec™) reduces phlebotomy requirements in polycythemia vera. Leukemia 2003; 17: 1186–1187.

    CAS  PubMed  Google Scholar 

  125. Cortes J, Giles F, O’Brien S, Thomas D, Albitar M, Rios MB et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer 2003; 97: 2760–2766.

    CAS  PubMed  Google Scholar 

  126. Tefferi A, Mesa RA, Gray LA, Steensma DP, Camoriano JK, Elliott MA et al. Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood 2002; 99: 3854–3856.

    CAS  PubMed  Google Scholar 

  127. Grandage VL, Everington T, Linch DC, Khwaja A . Go6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells. Br J Haematol 2006; 135: 303–316.

    CAS  PubMed  Google Scholar 

  128. Li Z, Xu M, Xing S, Ho WT, Ishii T, Li Q et al. Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth. J Biol Chem 2006; 282: 3428–3432.

    PubMed  Google Scholar 

  129. Giles F, Freedman SJ, Xiao A, Borthakur G, Garcia-Manero G, Wierda W et al. MK-0457, a novel multikinase inhibitor, has activity in refractory AML, including transformed JAK2 positive myeloproliferative disease (MPD), and in Philadelphia-positive ALL [abstract]. Blood 2006; 108: 1967a.

    Google Scholar 

  130. Dobrzanski P, Hexner E, Serdikoff C, Jan M, Swider C, Robinson C et al. CEP-701 Is a JAK2 inhibitor which attenuates JAK2/STAT5 signaling pathway and the proliferation of primary cells from patients with myeloproliferative disorders [abstract]. Blood 2006; 108: 3594a.

    Google Scholar 

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Acknowledgements

This research was supported by California Institute for Regenerative Medicine (CHMJ), Mizrahi Family Foundation (CFB), Moores UCSD Cancer Center Intramural Program (CJ).

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  1. Department of Medicine, Moores UCSD Cancer Center San Diego Medical Center, University of California, La Jolla, CA, USA

    C H M Jamieson & C F Barroga

  2. INSERM, Hématopoïèse et cellules souches, UMR790, Villejuif, France

    W P Vainchenker

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  1. C H M Jamieson
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  2. C F Barroga
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Correspondence to C H M Jamieson.

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Jamieson, C., Barroga, C. & Vainchenker, W. Miscreant myeloproliferative disorder stem cells. Leukemia 22, 2011–2019 (2008). https://doi.org/10.1038/leu.2008.290

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