title: Myeloproliferative disorders.
abstract: In 1951 William Dameshek classified polycythemia vera (PV), essential thombocytosis (ET), and primary myelofibrosis (PMF) as pathogenetically related myeloproliferative disorders (MPD). Subsequent studies demonstrated that PV, ET, and PMF are clonal disorders of multipotent hematopoietic progenitors. In 2005, a somatic activating mutation in the JAK2 nonreceptor tyrosine kinase (JAK2V617F) was identified in most patients with PV and in a significant proportion of patients with ET and PMF. Subsequent studies identified additional mutations in the JAK-STAT pathway in some patients with JAK2V617F(-) MPD, suggesting that constitutive activation of this signaling pathway is a unifying feature of these disorders. Although the discovery of mutations in the JAK-STAT pathway is important from a pathogenetic and diagnostic perspective, important questions remain regarding the role of this single disease allele in 3 related but clinically distinct disorders, and the role of additional genetic events in MPD disease pathogenesis. In addition, these observations provide a foundation for development of small molecule inhibitors of JAK2 that are currently being tested in clinical trials. This review will discuss our understanding of the pathogenesis of PV, ET, and PMF, the potential role of JAK2-targeted therapy, and the important unanswered questions that need to be addressed to improve clinical outcome.
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. leviner@mskcc.org
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000266:history; D011087:Polycythemia Vera; D055728:Primary Myelofibrosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D013922:Thrombocytosis
chemical_list: D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2
references.citation: Lancet. 2005 Mar 19-25;365(9464):1054-61
references.pmid: 15781101
references.citation: Blood. 2002 Aug 15;100(4):1123-32
references.pmid: 12149188
references.citation: Blood. 2007 Jul 1;110(1):375-9
references.pmid: 17363731
references.citation: Leukemia. 2008 Apr;22(4):740-7
references.pmid: 18079739
references.citation: Haematologica. 2007 Dec;92(12):1607-14
references.pmid: 18055983
references.citation: Semin Hematol. 1986 Jul;23(3):172-6
references.pmid: 3749927
references.citation: N Engl J Med. 2006 Jun 15;354(24):2542-51
references.pmid: 16775235
references.citation: Blood Cells Mol Dis. 2007 May-Jun;38(3):280-6
references.pmid: 17350297
references.citation: PLoS Med. 2006 Jul;3(7):e270
references.pmid: 16834459
references.citation: Blood. 2007 Mar 15;109(6):2310-3
references.pmid: 17110452
references.citation: Nature. 2005 Apr 28;434(7037):1144-8
references.pmid: 15793561
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6848-52
references.pmid: 1862109
references.citation: Blood. 2006 Aug 15;108(4):1377-80
references.pmid: 16675710
references.citation: Science. 2004 Jul 16;305(5682):399-401
references.pmid: 15256671
references.citation: N Engl J Med. 1995 Apr 27;332(17):1132-6
references.pmid: 7700286
references.citation: Blood. 2006 Oct 15;108(8):2770-9
references.pmid: 16804112
references.citation: Blood. 2006 Sep 1;108(5):1652-60
references.pmid: 16670266
references.citation: Br J Haematol. 1994 Feb;86(2):253-8
references.pmid: 7911034
references.citation: Blood. 2006 May 15;107(10):4139-41
references.pmid: 16434490
references.citation: Blood. 2005 Nov 15;106(10):3377-9
references.pmid: 16081687
references.citation: Nature. 1973 Jun 1;243(5405):290-3
references.pmid: 4126434
references.citation: Blood. 2004 Jun 1;103(11):4198-200
references.pmid: 14764528
references.citation: Blood. 2008 May 15;111(10):5109-17
references.pmid: 18334677
references.citation: N Engl J Med. 1974 Jun 13;290(24):1382
references.pmid: 4827655
references.citation: Cancer Res. 2000 Feb 1;60(3):549-52
references.pmid: 10676635
references.citation: Cell. 1998 May 1;93(3):385-95
references.pmid: 9590173
references.citation: Cell. 1993 Jul 30;74(2):227-36
references.pmid: 8343951
references.citation: Blood. 2008 Apr 15;111(8):3931-40
references.pmid: 18160670
references.citation: Lancet. 2005 Dec 3;366(9501):1945-53
references.pmid: 16325696
references.citation: Blood. 2006 Nov 15;108(10):3548-55
references.pmid: 16873677
references.citation: Exp Hematol. 2008 Feb;36(2):158-71
references.pmid: 18206727
references.citation: N Engl J Med. 1976 Oct 21;295(17):913-6
references.pmid: 967201
references.citation: Exp Hematol. 2004 Feb;32(2):179-87
references.pmid: 15102479
references.citation: Exp Hematol. 2007 May;35(5):702-11
references.pmid: 17577920
references.citation: Cell. 1993 Jul 30;74(2):237-44
references.pmid: 8343952
references.citation: Blood. 2006 Jun 1;107(11):4274-81
references.pmid: 16478879
references.citation: Cancer Cell. 2005 Apr;7(4):387-97
references.pmid: 15837627
references.citation: Cancer Cell. 2008 Apr;13(4):311-20
references.pmid: 18394554
references.citation: Cancer Res. 2007 Jul 1;67(13):6417-24
references.pmid: 17616702
references.citation: N Engl J Med. 1998 Feb 26;338(9):564-71
references.pmid: 9475763
references.citation: Blood. 2005 Aug 1;106(3):996-1002
references.pmid: 15831699
references.citation: Mol Cell. 2004 Jan 30;13(2):169-78
references.pmid: 14759363
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18962-7
references.pmid: 16365288
references.citation: Nature. 1995 Sep 7;377(6544):65-8
references.pmid: 7659163
references.citation: Blood. 2006 Oct 1;108(7):2435-7
references.pmid: 16772604
references.citation: N Engl J Med. 2005 Jul 7;353(1):33-45
references.pmid: 16000354
references.citation: Br J Haematol. 1995 May;90(1):131-7
references.pmid: 7786775
references.citation: Blood. 2006 Nov 15;108(10):3472-6
references.pmid: 16868251
references.citation: N Engl J Med. 1981 Feb 19;304(8):441-7
references.pmid: 7005681
references.citation: Protein Eng. 2001 Jan;14(1):27-37
references.pmid: 11287676
references.citation: J Clin Invest. 1977 May;59(5):841-8
references.pmid: 853125
references.citation: Blood. 2006 Sep 1;108(5):1551-4
references.pmid: 16684963
references.citation: J Biol Chem. 2008 May 9;283(19):12941-8
references.pmid: 18326042
references.citation: Blood. 2007 Mar 1;109(5):2202-4
references.pmid: 17068151
references.citation: Blood. 2005 Aug 15;106(4):1207-9
references.pmid: 15860661
references.citation: N Engl J Med. 2004 Jan 8;350(2):114-24
references.pmid: 14711910
references.citation: Blood. 2003 Apr 1;101(7):2784-8
references.pmid: 12456503
references.citation: Blood. 1996 Feb 15;87(4):1561-70
references.pmid: 8608248
references.citation: Blood. 1997 Jun 15;89(12):4628-35
references.pmid: 9192789
references.citation: N Engl J Med. 2007 Feb 1;356(5):459-68
references.pmid: 17267906
references.citation: Blood. 2006 Jul 1;108(1):346-52
references.pmid: 16537803
references.citation: J Biol Chem. 2002 Dec 6;277(49):47954-63
references.pmid: 12351625
references.citation: Blood. 2008 Mar 1;111(5):2785-9
references.pmid: 18006699
references.citation: Blood. 2006 Mar 1;107(5):1864-71
references.pmid: 16249382
references.citation: N Engl J Med. 2001 Apr 5;344(14):1038-42
references.pmid: 11287973
references.citation: Acta Haematol. 1979;62(2):94-9
references.pmid: 119408
references.citation: Blood. 1994 Nov 1;84(9):3086-94
references.pmid: 7949181
references.citation: N Engl J Med. 1998 Feb 26;338(9):572-80
references.pmid: 9475764
references.citation: Blood. 2005 Nov 15;106(10):3370-3
references.pmid: 16037387
references.citation: Proc Natl Acad Sci U S A. 1967 Oct;58(4):1468-71
references.pmid: 5237880
references.citation: Blood. 2008 Feb 1;111(3):1686-9
references.pmid: 17984312
references.citation: Semin Hematol. 1997 Jan;34(1):17-23
references.pmid: 9025158
references.citation: Blood. 2006 Jan 1;107(1):176-83
references.pmid: 16174768
references.citation: Blood. 2005 Oct 15;106(8):2920-1
references.pmid: 16204151
references.citation: Immunity. 2006 Nov;25(5):745-55
references.pmid: 17088085
references.citation: Blood. 2007 Mar 15;109(6):2446-52
references.pmid: 17105814
references.citation: Science. 1995 Nov 3;270(5237):797-800
references.pmid: 7481768
references.citation: Am J Med Sci. 2008 Jun;335(6):411-7
references.pmid: 18552568
references.citation: Exp Hematol. 2002 Mar;30(3):229-36
references.pmid: 11882360
references.citation: Leukemia. 2007 Aug;21(8):1658-68
references.pmid: 17541402
references.citation: Blood. 2008 Aug 1;112(3):844-7
references.pmid: 18519816
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6910-5
references.pmid: 9192665
references.citation: N Engl J Med. 2001 Apr 5;344(14):1031-7
references.pmid: 11287972
references.citation: Blood. 2000 Apr 15;95(8):2569-76
references.pmid: 10753836
references.citation: Blood. 2008 Jul 1;112(1):141-9
references.pmid: 18451306
references.citation: Blood. 2003 Nov 15;102(10):3793-6
references.pmid: 12829587
references.citation: Br J Haematol. 2007 May;137(3):244-7
references.pmid: 17408465
references.citation: Exp Hematol. 2007 Nov;35(11):1695-703
references.pmid: 17764814
references.citation: Blood. 2006 Sep 15;108(6):2037-40
references.pmid: 16709929
references.citation: Blood. 1951 Apr;6(4):372-5
references.pmid: 14820991
references.citation: Mol Cell. 2000 Sep;6(3):693-704
references.pmid: 11030348
references.citation: N Engl J Med. 2005 Apr 28;352(17):1779-90
references.pmid: 15858187