臨床検査54巻3号

2010年03月発行

今月の主題 骨髄増殖性疾患 各論 〈病態―新しい研究の展開〉

真性多血症

著者： 小松則夫¹

所属機関： ¹順天堂大学医学部附属順天堂医院血液内科

ページ範囲：P.247 - P.254

　JAK2遺伝子変異(V617F)は真性多血症，本態性血小板血症や原発性骨髄線維症に共通してがみられる．JAK2はエリスロポエチンなどのサイトカイン細胞内シグナル伝達の中心的役割を担うチロシンキナーゼで，V617F変異はキナーゼ活性を負に制御するJH2領域にアミノ酸置換があり，高いチロシンキナーゼ活性が持続し，血球増加をきたす．この変異は真性多血症のほぼ全例に認められ，最近ではJAK2エクソン12の変異も報告されている．いずれもSTAT5を含む様々なシグナル伝達分子の恒常的な活性化を認める．さらに，細胞内シグナルを負に制御するSOCS分子の発現異常も真性多血症の病態に関与している可能性がある．

参考文献

1) DAMESHEK W：Some speculations on the myeloproliferative syndromes. Blood　6：372-375, 1951

2) Baxter EJ, Scott LM, Campbell PJ, et al：Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet　365：1054-1061, 2005

3) James C, Ugo V, Le Couedic JP, et al：A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature　434：1144-1148, 2005

4) 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　7：387-397, 2005

5) Kralovics R, Passamonti F, Buser AS, et al：A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med　352：1779-1790, 2005

6) Zhao R, Xing S, Li Z, et al：Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem　280：22788-22792, 2005

7) Scott LM, Tong W, Levine RL, et al：JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med　356：459-468, 2007

8) Swerdlow SH, Campo E, Harris NL, et al (eds)：WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization, Lyon, pp40-43, 2008

9) Wilks AF：Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc Natl Acad Sci U S A　86：1603-1607, 1989

10) Neubauer H, Cumano A, Muller M, et al：Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell　93：397-409, 1998

11) 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　74：227-236, 1993

12) Baker SJ, Rane SG, Reddy EP：Hematopoietic cytokine receptor signaling. Oncogene　26：6724-6737, 2007

13) 小松則夫：骨髄増殖性疾患の病態．日本検査血液学雑誌　10：375-382，2009

14) Saharinen P, Vihinen M, Silvennoinen O：Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. Mol Biol Cell　14：1448-1459, 2003

15) Goerttler PS, Steimle C, März E, et al：The Jak2V617F mutation, PRV-1 overexpression, and EEC formation define a similar cohort of MPD patients. Blood　106：2862-2864, 2005

16) 小松則夫：病態と治療 真性赤血球増加症．日内会誌　96：1382-1389，2007

17) Staerk J, Kallin A, Demoulin JB, et al：JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation：cross-talk with IGF1 receptor. J Biol Chem　280：41893-41899, 2005

18) Laubach JP, Fu P, Jiang X, et al：Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation. Exp Hematol　37：1411-1422, 2009

19) Zeuner A, Pedini F, Signore M, et al：Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells. Blood　107：3495-3502, 2006

20) Zaleskas VM, Krause DS, Lazarides K, et al：Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F. PLoS One　1：e18, 2006

21) Wood AD, Chen E, Donaldson IJ, et al：ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling. Blood　114：1820-1830, 2009

22) Yoshimura A, Naka T, Kubo M：SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol　7：454-465, 2007

23) Starr R, Willson TA, Viney EM, et al：A family of cytokine-inducible inhibitors of signalling. Nature　387：917-921, 1997

24) Hookham MB, Elliott J, Suessmuth Y, et al：The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3. Blood　109：4924-4929, 2007

25) Elliott J, Suessmuth Y, Scott LM, et al：SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases. Haematologica　94：576-580, 2009

26) Suessmuth Y, Elliott J, Percy MJ, et al：A new polycythaemia vera-associated SOCS3 SH2 mutant(SOCS3F136L)cannot regulate erythropoietin responses. Br J Haematol　147：450-458, 2009

27) Teofili L, Martini M, Cenci T, et al：Epigenetic alteration of SOCS family members is a possible pathogenetic mechanism in JAK2 wild type myeloproliferative diseases. Int J Cancer　123：1586-1592, 2008

28) Jost E, do O N, Dahl E, et al：Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders. Leukemia　21：505-510, 2007

29) Pietra D, Li S, Brisci A, et al：Somatic mutations of JAK2 exon 12 in patients with JAK2(V617F)-negative myeloproliferative disorders. Blood　111：1686-1689, 2008

30) Martínez-Avilés L, Besses C, Alvarez-Larrán A, et al：JAK2 exon 12 mutations in polycythemia vera or idiopathic erythrocytosis. Haematologica　92：1717-1718, 2007

31) Percy MJ, Scott LM, Erber WN, et al：The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels. Haematologica　92：1607-1614, 2007

32) Delhommeau F, Dupont S, Della Valle V, et al：Mutation in TET2 in myeloid cancers. N Engl J Med　360：2289-2301, 2009

33) Saint-Martin C, Leroy G, Delhommeau F, et al：Analysis of the ten-eleven translocation 2(TET2)gene in familial myeloproliferative neoplasms. Blood　114：1628-1632, 2009

34) Bruchova H, Merkerova M, Prchal JT：Aberrant expression of microRNA in polycythemia vera. Haematologica　93：1009-1016, 2008