Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Molecular pathogenesis of congenital polycythemic disorders and polycythemia vera

Josef T Prchal, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Alan G Rosmarin, MD


Absolute polycythemia refers to settings in which there is an increase in red cell mass. This condition has also been called erythrocytosis, with three forms being recognized (table 1):

Primary polycythemia – Primary polycythemia is caused by acquired (somatic) or inherited (germline) mutations expressed within the erythroid progenitors that increase their proliferation and cause accumulation of erythrocytes (ie, polycythemia). Such mutations occur in polycythemia vera and in dominantly inherited polycythemias caused by "gain-of-function" mutations of the erythropoietin receptor gene (EPOR). Primary polycythemias can be distinguished from secondary polycythemias by in vitro assays that reveal proliferation of erythroid progenitors with minimal or no added erythropoietin (EPO).

Secondary polycythemia – Secondary polycythemia refers to conditions in which there are circulating plasma factors that stimulate erythropoiesis (eg, EPO, testosterone). In rare instances, exposure to cobalt, dysregulated angiotensin/angiotensin receptor 1 erythroid signaling (eg, in postrenal transplant erythrocytosis), or elevated plasma levels of insulin-like growth factor-1 can stimulate erythropoiesis.

Secondary polycythemia can be "appropriate" or "inappropriate" physiological responses, and both categories include both acquired and congenital causes. Examples include appropriate physiological response to tissue hypoxia (eg, low hemoglobin oxygen saturation from lung disease, high carboxy-hemoglobin in cigarette smokers) or congenital causes (eg, mutant hemoglobin with increased oxygen affinity; inherited defect of 2,3 BPG [2,3 DPG] synthesis). Examples of inappropriate responses include EPO-secreting tumors or increased EPO due to congenital disorders of hypoxia sensing.

Mixed (ie, primary and secondary) congenital disorders of hypoxia sensing – Some disorders share features of both primary (ie, increased sensitivity of erythroid progenitors to EPO) and secondary polycythemia (ie, elevated EPO levels). Examples include Chuvash polycythemia, other congenital von Hippel Lindau (VHL) gene mutations, and gain-of-function mutations of EPAS1 (encoding hypoxia inducible factor HIF-2 alpha).

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Dec 06, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Eaves CJ, Eaves AC. Erythropoietin (Ep) dose-response curves for three classes of erythroid progenitors in normal human marrow and in patients with polycythemia vera. Blood 1978; 52:1196.
  2. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995; 83:59.
  3. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292:468.
  4. Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292:464.
  5. Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med 2011; 365:537.
  6. Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood 2013; 122:1122.
  7. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995; 92:5510.
  8. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270:1230.
  9. Yoon D, Ponka P, Prchal JT. Hypoxia. 5. Hypoxia and hematopoiesis. Am J Physiol Cell Physiol 2011; 300:C1215.
  10. Semenza GL. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood 2009; 114:2015.
  11. Jones SS, D'Andrea AD, Haines LL, Wong GG. Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood 1990; 76:31.
  12. Koury MJ, Bondurant MC. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 1990; 248:378.
  13. D'Andrea AD, Yoshimura A, Youssoufian H, et al. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol 1991; 11:1980.
  14. Witthuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 1993; 74:227.
  15. Klingmüller U, Lorenz U, Cantley LC, et al. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 1995; 80:729.
  16. Gregg XT, Prchal JT. Erythropoietin receptor mutations and human disease. Semin Hematol 1997; 34:70.
  17. Arcasoy MO, Degar BA, Harris KW, Forget BG. Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene. Blood 1997; 89:4628.
  18. Kralovics R, Indrak K, Stopka T, et al. Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood 1997; 90:2057.
  19. Prchal JT. Classification and molecular biology of polycythemias (erythrocytoses) and thrombocytosis. Hematol Oncol Clin North Am 2003; 17:1151.
  20. Sawada K, Krantz SB, Dessypris EN, et al. Human colony-forming units-erythroid do not require accessory cells, but do require direct interaction with insulin-like growth factor I and/or insulin for erythroid development. J Clin Invest 1989; 83:1701.
  21. Correa PN, Axelrad AA. Production of erythropoietic bursts by progenitor cells from adult human peripheral blood in an improved serum-free medium: role of insulinlike growth factor 1. Blood 1991; 78:2823.
  22. Shih LY, Huang JY, Lee CT. Insulin-like growth factor I plays a role in regulating erythropoiesis in patients with end-stage renal disease and erythrocytosis. J Am Soc Nephrol 1999; 10:315.
  23. Perazella M, McPhedran P, Kliger A, et al. Enalapril treatment of posttransplant erythrocytosis: efficacy independent of circulating erythropoietin levels. Am J Kidney Dis 1995; 26:495.
  24. Julian BA, Brantley RR Jr, Barker CV, et al. Losartan, an angiotensin II type 1 receptor antagonist, lowers hematocrit in posttransplant erythrocytosis. J Am Soc Nephrol 1998; 9:1104.
  25. Gossmann J, Thürmann P, Bachmann T, et al. Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients. Kidney Int 1996; 50:973.
  26. Dhondt AW, Vanholder RC, Ringoir SM. Angiotensin-converting enzyme inhibitors and higher erythropoietin requirement in chronic haemodialysis patients. Nephrol Dial Transplant 1995; 10:2107.
  27. Mrug M, Stopka T, Julian BA, et al. Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 1997; 100:2310.
  28. Marrero MB, Schieffer B, Paxton WG, et al. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 1995; 375:247.
  29. Semenza GL. Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med 2010; 2:336.
  30. Poliakova LA. [Familial erythrocytosis among the residents of the Chuvash ASSR]. Probl Gematol Pereliv Krovi 1974; 19:30.
  31. Sergeyeva A, Gordeuk VR, Tokarev YN, et al. Congenital polycythemia in Chuvashia. Blood 1997; 89:2148.
  32. Pastore YD, Jelinek J, Ang S, et al. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood 2003; 101:1591.
  33. Perrotta S, Nobili B, Ferraro M, et al. Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. Blood 2006; 107:514.
  34. Pastore Y, Jedlickova K, Guan Y, et al. Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet 2003; 73:412.
  35. Percy MJ, McMullin MF, Jowitt SN, et al. Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry. Blood 2003; 102:1097.
  36. Gordeuk VR, Stockton DW, Prchal JT. Congenital polycythemias/erythrocytoses. Haematologica 2005; 90:109.
  37. Gordeuk VR, Sergueeva AI, Miasnikova GY, et al. Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 2004; 103:3924.
  38. Sergueeva AI, Miasnikova GY, Polyakova LA, et al. Complications in children and adolescents with Chuvash polycythemia. Blood 2015; 125:414.
  39. Ang SO, Chen H, Hirota K, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 2002; 32:614.
  40. Gordeuk VR, Miasnikova GY, Sergueeva AI, et al. Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression. Blood 2011; 118:5278.
  41. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007; 117:1926.
  42. Sergueeva A, Miasnikova G, Shah BN, et al. Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia. Haematologica 2017; 102:e166.
  43. Zhou AW, Knoche EM, Engle EK, et al. Clinical Improvement with JAK2 Inhibition in Chuvash Polycythemia. N Engl J Med 2016; 375:494.
  44. Ang SO, Chen H, Gordeuk VR, et al. Endemic polycythemia in Russia: mutation in the VHL gene. Blood Cells Mol Dis 2002; 28:57.
  45. Ladroue C, Hoogewijs D, Gad S, et al. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica 2012; 97:9.
  46. Tomasic NL, Piterkova L, Huff C, et al. The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W). Haematologica 2013; 98:560.
  47. Lanikova L, Lorenzo F, Yang C, et al. Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer. Blood 2013; 121:3918.
  48. Lorenzo FR, Yang C, Lanikova L, et al. Novel compound VHL heterozygosity (VHL T124A/L188V) associated with congenital polycythaemia. Br J Haematol 2013; 162:851.
  49. Prchal JT. Clinical manifestations and classification of erythrocyte disorders. In: Williams Hematology, 8th ed, Kaushansky K, Lichtman MA, Kipps TJ, et al (Eds), McGraw Hill, New York 2010. p.455.
  50. Percy MJ, Zhao Q, Flores A, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A 2006; 103:654.
  51. Albiero E, Ruggeri M, Fortuna S, et al. Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. Haematologica 2012; 97:123.
  52. Hsieh MM, Linde NS, Wynter A, et al. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood 2007; 110:2140.
  53. Minamishima YA, Moslehi J, Bardeesy N, et al. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 2008; 111:3236.
  54. Takeda K, Aguila HL, Parikh NS, et al. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 2008; 111:3229.
  55. Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010; 21:2151.
  56. Querbes W, Bogorad RL, Moslehi J, et al. Treatment of erythropoietin deficiency in mice with systemically administered siRNA. Blood 2012; 120:1916.
  57. Ladroue C, Carcenac R, Leporrier M, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med 2008; 359:2685.
  58. Lorenzo FR, Huff C, Myllymäki M, et al. A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 2014; 46:951.
  59. Percy MJ, Furlow PW, Lucas GS, et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 2008; 358:162.
  60. Percy MJ, Beer PA, Campbell G, et al. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood 2008; 111:5400.
  61. Gale DP, Harten SK, Reid CD, et al. Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. Blood 2008; 112:919.
  62. Perrotta S, Stiehl DP, Punzo F, et al. Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range. Haematologica 2013; 98:1624.
  63. Eltzschig HK, El Kasmi KC, Eckle T. The HIF2A gene in familial erythrocytosis. N Engl J Med 2008; 358:1965.
  64. Zhuang Z, Yang C, Lorenzo F, et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012; 367:922.
  65. Yang C, Sun MG, Matro J, et al. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood 2013; 121:2563.
  66. Pacak K, Jochmanova I, Prodanov T, et al. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol 2013; 31:1690.
  67. Lorenzo FR, Yang C, Ng Tang Fui M, et al. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med (Berl) 2013; 91:507.
  68. Agarwal N, Mojica-Henshaw MP, Simmons ED, et al. Familial polycythemia caused by a novel mutation in the beta globin gene: essential role of P50 in evaluation of familial polycythemia. Int J Med Sci 2007; 4:232.
  69. Lichtman MA, Murphy MS, Adamson JW. Detection of mutant hemoglobins with altered affinity for oxygen. A simplified technique. Ann Intern Med 1976; 84:517.
  70. Agarwal N, Nagel RL, Prchal JT. Dyshemoglobinemias. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, 2nd ed, Steinberg M (Ed), Cambridge UP, Cambridge 2009. p.607.
  71. Rosa R, Prehu MO, Beuzard Y, Rosa J. The first case of a complete deficiency of diphosphoglycerate mutase in human erythrocytes. J Clin Invest 1978; 62:907.
  72. Galacteros F, Rosa R, Prehu MO, et al. [Diphosphoglyceromutase deficiency: new cases associated with erythrocytosis]. Nouv Rev Fr Hematol 1984; 26:69.
  73. Lemarchandel V, Joulin V, Valentin C, et al. Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency. Blood 1992; 80:2643.
  74. Emanuel PD, Eaves CJ, Broudy VC, et al. Familial and congenital polycythemia in three unrelated families. Blood 1992; 79:3019.
  75. Juvonen E, Ikkala E, Fyhrquist F, Ruutu T. Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin. Blood 1991; 78:3066.
  76. Huang LJ, Shen YM, Bulut GB. Advances in understanding the pathogenesis of primary familial and congenital polycythaemia. Br J Haematol 2010; 148:844.
  77. Damen JE, Krosl J, Morrison D, et al. The hyperresponsiveness of cells expressing truncated erythropoietin receptors is contingent on insulin-like growth factor-1 in fetal calf serum. Blood 1998; 92:425.
  78. Divoky V, Liu Z, Ryan TM, et al. Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene. Proc Natl Acad Sci U S A 2001; 98:986.
  79. Kralovics R, Prchal JT. Genetic heterogeneity of primary familial and congenital polycythemia. Am J Hematol 2001; 68:115.
  80. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006; 355:2452.
  81. Schafer AI. Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia. Blood 2006; 107:4214.
  82. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434:1144.
  83. Adamson JW, Fialkow PJ, Murphy S, et al. Polycythemia vera: stem-cell and probable clonal origin of the disease. N Engl J Med 1976; 295:913.
  84. Swierczek S, Lima LT, Tashi T, et al. Presence of polyclonal hematopoiesis in females with Ph-negative myeloproliferative neoplasms. Leukemia 2015; 29:2432.
  85. Prchal JT. Polycythemia vera and other primary polycythemias. Curr Opin Hematol 2005; 12:112.
  86. Prchal JF, Axelrad AA. Letter: Bone-marrow responses in polycythemia vera. N Engl J Med 1974; 290:1382.
  87. Weinberg RS. In vitro erythropoiesis in polycythemia vera and other myeloproliferative disorders. Semin Hematol 1997; 34:64.
  88. Westwood NB, Pearson TC. Diagnostic applications of haemopoietic progenitor culture techniques in polycythaemias and thrombocythaemias. Leuk Lymphoma 1996; 22 Suppl 1:95.
  89. Shih LY, Lee CT, See LC, et al. In vitro culture growth of erythroid progenitors and serum erythropoietin assay in the differential diagnosis of polycythaemia. Eur J Clin Invest 1998; 28:569.
  90. Shih LY, Lee CT. Identification of masked polycythemia vera from patients with idiopathic marked thrombocytosis by endogenous erythroid colony assay. Blood 1994; 83:744.
  91. Zanjani ED, Lutton JD, Hoffman R, Wasserman LR. Erythroid colony formation by polycythemia vera bone marrow in vitro. Dependence on erythropoietin. J Clin Invest 1977; 59:841.
  92. Prchal JT, Crist WM, Goldwasser E, et al. Autosomal dominant polycythemia. Blood 1985; 66:1208.
  93. Fisher MJ, Prchal JF, Prchal JT, D'Andrea AD. Anti-erythropoietin (EPO) receptor monoclonal antibodies distinguish EPO-dependent and EPO-independent erythroid progenitors in polycythemia vera. Blood 1994; 84:1982.
  94. Liu E, Jelinek J, Pastore YD, et al. Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. Blood 2003; 101:3294.
  95. Kralovics R, Buser AS, Teo SS, et al. Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders. Blood 2003; 102:1869.
  96. Correa PN, Eskinazi D, Axelrad AA. Circulating erythroid progenitors in polycythemia vera are hypersensitive to insulin-like growth factor-1 in vitro: studies in an improved serum-free medium. Blood 1994; 83:99.
  97. Mirza AM, Ezzat S, Axelrad AA. Insulin-like growth factor binding protein-1 is elevated in patients with polycythemia vera and stimulates erythroid burst formation in vitro. Blood 1997; 89:1862.
  98. 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.
  99. Miller RL, Purvis JD 3rd, Weick JK. Familial polycythemia vera. Cleve Clin J Med 1989; 56:813.
  100. Brubaker LH, Wasserman LR, Goldberg JD, et al. Increased prevalence of polycythemia vera in parents of patients on polycythemia vera study group protocols. Am J Hematol 1984; 16:367.
  101. Kralovics R, Stockton DW, Prchal JT. Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 2003; 102:3793.
  102. Tashi T, Swierczek S, Prchal JT. Familial MPN Predisposition. Curr Hematol Malig Rep 2017; 12:442.
  103. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002; 3:651.
  104. Khwaja A. The role of Janus kinases in haemopoiesis and haematological malignancy. Br J Haematol 2006; 134:366.
  105. Neubauer H, Cumano A, Müller M, et al. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93:397.
  106. Damen JE, Wakao H, Miyajima A, et al. Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. EMBO J 1995; 14:5557.
  107. Lacronique V, Boureux A, Valle VD, et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997; 278:1309.
  108. Peeters P, Raynaud SD, Cools J, et al. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 1997; 90:2535.
  109. Ugo V, Marzac C, Teyssandier I, et al. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol 2004; 32:179.
  110. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365:1054.
  111. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7:387.
  112. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352:1779.
  113. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005; 280:22788.
  114. Wernig G, Mercher T, Okabe R, et al. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006; 107:4274.
  115. Lacout C, Pisani DF, Tulliez M, et al. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood 2006; 108:1652.
  116. Akada H, Yan D, Zou H, et al. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood 2010; 115:3589.
  117. Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 2008; 111:3931.
  118. Bellanné-Chantelot C, Chaumarel I, Labopin M, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 2006; 108:346.
  119. Pietra D, Casetti I, Da Vià MC, et al. JAK2 GGCC haplotype in MPL mutated myeloproliferative neoplasms. Am J Hematol 2012; 87:746.
  120. Wang L, Swierczek SI, Lanikova L, et al. The relationship of JAK2(V617F) and acquired UPD at chromosome 9p in polycythemia vera. Leukemia 2014; 28:938.
  121. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356:459.
  122. Pietra D, Li S, Brisci A, et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008; 111:1686.
  123. Scott LM. The JAK2 exon 12 mutations: a comprehensive review. Am J Hematol 2011; 86:668.
  124. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes. Blood 2005; 106:1207.
  125. Jelinek J, Oki Y, Gharibyan V, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood 2005; 106:3370.
  126. Kralovics R, Teo SS, Li S, et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 2006; 108:1377.
  127. Rumi E, Passamonti F, Pietra D, et al. JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders. Cancer 2006; 107:2206.
  128. Spivak JL, Considine M, Williams DM, et al. Two clinical phenotypes in polycythemia vera. N Engl J Med 2014; 371:808.
  129. Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood 2011; 118:1723.
  130. Wang L, Swierczek SI, Drummond J, et al. Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. Leukemia 2014; 28:935.
  131. Vannucchi AM, Biamonte F. Epigenetics and mutations in chronic myeloproliferative neoplasms. Haematologica 2011; 96:1398.
  132. Makishima H, Visconte V, Sakaguchi H, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012; 119:3203.
  133. Zhang SJ, Rampal R, Manshouri T, et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 2012; 119:4480.