Skip to main content
SpringerLink
Log in

Pathogenesis of Clonal Dominance in PNH: Growth Advantage in PNH

  • Chapter
  • First Online:
Paroxysmal Nocturnal Hemoglobinuria

  • 669 Accesses

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI)-deficient hematopoietic stem cells (HSCs). Although the deficiency in GPI caused by a somatic mutation in phosphatidylinositol glycan-class A (PIGA) can clearly account for the characteristic manifestation of intravascular hemolysis induced by complement attack in patients with PNH, additional abnormalities must be involved in the clonal expansion of GPI-deficient HSCs. Several reports have shown additional abnormalities predicted to be involved in the growth advantage of GPI-deficient HSCs in PNH. One of the best candidates is HMGA2, a gene encoding an architectural transcriptional regulator that is deregulated in many benign mesenchymal tumors. The aberrant expression of HMGA2 in PNH clones suggests that PNH may be viewed as a benign tumor of bone marrow cells. WT1 transcript upregulation and JAK2 p.V617F somatic mutation, observed in the other hematopoietic malignancies such as myeloproliferative neoplasms and myelodysplastic syndrome, have also been observed in some patients with PNH. In a recent whole-exome sequencing analysis, an average of two additional somatic mutations were observed in patients with PNH, and somatic mutations in many genes identified in other hematopoietic malignancies have been found. No gene abnormality has been found to be common to all patients with PNH. Further epigenetic and genetic analyses are necessary to clarify the general molecular mechanism involved in the expansion of PNH clones.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Brodsky RA (2014) Paroxysmal nocturnal hemoglobinuria. Blood 124 (18):2804–2811. doi:blood-2014-02-522128 [pii]10.1182/blood-2014-02-522128

  2. Kawagoe K, Kitamura D, Okabe M, Taniuchi I, Ikawa M, Watanabe T, Kinoshita T, Takeda J (1996) Glycosylphosphatidylinositol-anchor-deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 87(9):3600–3606

    CAS  PubMed  Google Scholar 

  3. Rosti V, Tremml G, Soares V, Pandolfi PP, Luzzatto L, Bessler M (1997) Murine embryonic stem cells without pig-a gene activity are competent for hematopoiesis with the PNH phenotype but not for clonal expansion. J Clin Invest 100(5):1028–1036. doi:10.1172/JCI119613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Murakami Y, Kinoshita T, Maeda Y, Nakano T, Kosaka H, Takeda J (1999) Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria. Blood 94(9):2963–2970

    CAS  PubMed  Google Scholar 

  5. Tremml G, Dominguez C, Rosti V, Zhang Z, Pandolfi PP, Keller P, Bessler M (1999) Increased sensitivity to complement and a decreased red blood cell life span in mice mosaic for a nonfunctional Piga gene. Blood 94(9):2945–2954

    CAS  PubMed  Google Scholar 

  6. Keller P, Tremml G, Rosti V, Bessler M (1999) X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation. Proc Natl Acad Sci U S A 96(13):7479–7483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sugimori C, Chuhjo T, Feng X, Yamazaki H, Takami A, Teramura M, Mizoguchi H, Omine M, Nakao S (2006) Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood 107 (4):1308–1314. doi:2005-06-2485 [pii] 10.1182/blood-2005-06-2485

  8. Murakami Y, Kosaka H, Maeda Y, Nishimura J, Inoue N, Ohishi K, Okabe M, Takeda J, Kinoshita T (2002) Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria. Blood 100 (12):4116–4122. doi: 10.1182/blood-2002-06-1669 2002-06-1669 [pii]

  9. Hanaoka N, Kawaguchi T, Horikawa K, Nagakura S, Mitsuya H, Nakakuma H (2006) Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP. Blood 107(3):1184–1191. doi:2005-03-1337 [pii] 10.1182/blood-2005-03-1337

  10. Ikeda K, Shichishima T, Yasukawa M, Nakamura-Shichishima A, Noji H, Akutsu K, Osumi K, Maruyama Y (2007) The role of Wilms’ tumor gene peptide-specific cytotoxic T lymphocytes in immunologic selection of a paroxysmal nocturnal hemoglobinuria clone. Exp Hematol 35(4):618–626. doi: S0301-472X(07)00056-2 [pii] 10.1016/j.exphem.2007.01.045

  11. Gargiulo L, Papaioannou M, Sica M, Talini G, Chaidos A, Richichi B, Nikolaev AV, Nativi C, Layton M, de la Fuente J, Roberts I, Luzzatto L, Notaro R, Karadimitris A (2013) Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria. Blood 121(14):2753–2761. doi:blood-2012-11-469353 [pii] 10.1182/blood-2012-11-469353

  12. Okamoto M, Shichishima T, Noji H, Ikeda K, Nakamura A, Akutsu K, Maruyama Y (2006) High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome. Leukemia 20(4):627–634. doi:2404135 [pii] 10.1038/sj.leu.2404135

  13. Nishimura J, Hirota T, Kanakura Y, Machii T, Kageyama R, Doi S, Wada H, Masaoka T, Kanayama Y, Fujii H, Inoue N, Kuwayama M, Inoue N, Ohishi K, Kinoshita T (2002) Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria. blood 99(8):2748–2751. doi:http://dx.doi.org/10.1182/blood.V99.8.2748

  14. Fusco A, Fedele M (2007) Roles of HMGA proteins in cancer. Nat Rev Cancer 7(12):899–910. doi:nrc2271 [pii]10.1038/nrc2271

  15. Inoue N, Izui-Sarumaru T, Murakami Y, Endo Y, Nishimura J, Kurokawa K, Kuwayama M, Shime H, Machii T, Kanakura Y, Meyers G, Wittwer C, Chen Z, Babcock W, Frei-Lahr D, Parker CJ, Kinoshita T (2006) Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood 108(13):4232–4236. doi:blood-2006-05-025148 [pii]10.1182/blood-2006-05-025148

  16. Nishimura JI, Inoue N, Azenishi Y, Hirota T, Akaogi T, Shibano M, Kawagoe K, Ueda E, Machii T, Takeda J (1996) Analysis of PIG-A gene in a patient who developed reciprocal translocation of chromosome 12 and paroxysmal nocturnal hemoglobinuria during follow-up of aplastic anemia. Am J Hematol 51(3):229–233. doi:10.1002/(SICI)1096-8652(199603)51:3<229::AID-AJH8>3.0.CO;2-Z [pii] 10.1002/(SICI)1096-8652(199603)51:3<229::AID-AJH8>3.0.CO;2-Z

  17. Ordulu Z, Wong KE, Currall BB, Ivanov AR, Pereira S, Althari S, Gusella JF, Talkowski ME, Morton CC (2014) Describing sequencing results of structural chromosome rearrangements with a suggested next-generation cytogenetic nomenclature. Am J Hum Genet 94 (5):695–709. doi: S0002-9297(14)00172-4 [pii] 10.1016/j.ajhg.2014.03.020

  18. Harris JW, Koscick R, Lazarus HM, Eshleman JR, Medof ME (1999) Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma 32(5–6):401–426. doi:10.3109/10428199909058399

    Article  CAS  PubMed  Google Scholar 

  19. Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H, Decastro CM, Hall S, Kanamaru A, Sullivan KM, Mizoguchi H, Omine M, Kinoshita T, Rosse WF (2004) Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 83(3):193–207. doi: 00005792-200405000-00005 [pii]

    Google Scholar 

  20. Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315(5818):1576–1579. doi:1137999 [pii] 10.1126/science.1137999

  21. Copley MR, Babovic S, Benz C, Knapp DJ, Beer PA, Kent DG, Wohrer S, Treloar DQ, Day C, Rowe K, Mader H, Kuchenbauer F, Humphries RK, Eaves CJ (2013) The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nat Cell Biol 15 (8):916–925. doi:ncb2783 [pii] 10.1038/ncb2783

  22. Murakami Y, Inoue N, Shichishima T, Ohta R, Noji H, Maeda Y, Nishimura J, Kanakura Y, Kinoshita T (2012) Deregulated expression of HMGA2 is implicated in clonal expansion of PIGA deficient cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol 156(3):383–387. doi:10.1111/j.1365-2141.2011.08914.x

    Article  CAS  PubMed  Google Scholar 

  23. Lam K, Muselman A, Du R, Harada Y, Scholl AG, Yan M, Matsuura S, Weng S, Harada H, Zhang DE (2014) Hmga2 is a direct target gene of RUNX1 and regulates expansion of myeloid progenitors in mice. Blood 124(14):2203–2212. doi: blood-2014-02-554543 [pii] 10.1182/blood-2014-02-554543

  24. Andrieux J, Demory JL, Dupriez B, Quief S, Plantier I, Roumier C, Bauters F, Lai JL, Kerckaert JP (2004) Dysregulation and overexpression of HMGA2 in myelofibrosis with myeloid metaplasia. Genes Chromosomes Cancer 39(1):82–87. doi:10.1002/gcc.10297

    Article  CAS  PubMed  Google Scholar 

  25. Odero MD, Grand FH, Iqbal S, Ross F, Roman JP, Vizmanos JL, Andrieux J, Lai JL, Calasanz MJ, Cross NC (2005) Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies. Leukemia 19(2):245–252. doi:2403605 [pii] 10.1038/sj.leu.2403605

  26. Storlazzi CT, Albano F, Locunsolo C, Lonoce A, Funes S, Guastadisegni MC, Cimarosto L, Impera L, D’Addabbo P, Panagopoulos I, Specchia G, Rocchi M (2006) t(3;12)(q26;q14) in polycythemia vera is associated with upregulation of the HMGA2 gene. Leukemia 20(12):2190–2192. doi: 2404418 [pii] 10.1038/sj.leu.2404418

  27. Martin SE, Sausen M, Joseph A, Kingham BF, Martin ES (2012) Identification of a HMGA2-EFCAB6 gene rearrangement following next-generation sequencing in a patient with a t(12;22)(q14.3;q13.2) and JAK2V617F-positive myeloproliferative neoplasm. Cancer Genet 205(6):295–303. doi:S2210-7762(12)00102-0 [pii] 10.1016/j.cancergen.2012.03.006

  28. Harada-Shirado K, Ikeda K, Ogawa K, Ohkawara H, Kimura H, Kai T, Noji H, Morishita S, Komatsu N, Takeishi Y (2015) Dysregulation of the MIRLET7/HMGA2 axis with methylation of the CDKN2A promoter in myeloproliferative neoplasms. Br J Haematol 168(3):338–349. doi:10.1111/bjh.13129

    Article  CAS  PubMed  Google Scholar 

  29. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chretien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chretien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, Leboulch P (2010) Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 467(7313):318–322. doi:nature09328 [pii] 10.1038/nature09328

  30. Payen E, Leboulch P (2012) Advances in stem cell transplantation and gene therapy in the beta-hemoglobinopathies. Hematol Am Soc Hematol Educ Program 2012:276–283. doi:2012/1/276 [pii] 10.1182/asheducation-2012.1.276

  31. Ikeda K, Mason PJ, Bessler M (2011) 3’UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice. Blood 117(22):5860–5869. doi: blood-2011-02-334425 [pii] 10.1182/blood-2011-02-334425

  32. Sugimori C, Padron E, Caceres G, Shain K, Sokol L, Zhang L, Tiu R, O’Keefe CL, Afable M, Clemente M, Lee JM, Maciejewski JP, List AF, Epling-Burnette PK, Araten DJ (2012) Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation. Blood Cancer J 2(3):e63. doi:10.1038/bcj.2012.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shen W, Clemente MJ, Hosono N, Yoshida K, Przychodzen B, Yoshizato T, Shiraishi Y, Miyano S, Ogawa S, Maciejewski JP, Makishima H (2014) Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest 124(10):4529–4538. doi: 74747 [pii] 10.1172/JCI74747

  34. Levine RL, Pardanani A, Tefferi A, Gilliland DG (2007) Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 7(9):673–683. doi:nrc2210 [pii] 10.1038/nrc2210

  35. Vainchenker W, Constantinescu SN (2013) JAK/STAT signaling in hematological malignancies. Oncogene 32(21):2601–2613. doi: onc2012347 [pii] 10.1038/onc.2012.347

  36. Ungureanu D, Wu J, Pekkala T, Niranjan Y, Young C, Jensen ON, Xu CF, Neubert TA, Skoda RC, Hubbard SR, Silvennoinen O (2011) The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol 18(9):971–976. doi: nsmb.2099 [pii] 10.1038/nsmb.2099

  37. O’Keefe CL, Sugimori C, Afable M, Clemente M, Shain K, Araten DJ, List A, Epling-Burnette PK, Maciejewski JP (2011) Deletions of Xp22.2 including PIG-A locus lead to paroxysmal nocturnal hemoglobinuria. Leukemia 25(2):379–382. doi:leu2010274 [pii] 10.1038/leu.2010.274

  38. Rivera MN, Haber DA (2005) Wilms’ tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer 5(9):699–712. doi:nrc1696 [pii] 10.1038/nrc1696

  39. Sugiyama H (2010) WT1 (Wilms’ tumor gene 1): biology and cancer immunotherapy. Jpn J Clin Oncol 40(5):377–387. doi: hyp194 [pii] 10.1093/jjco/hyp194

  40. Owen C, Fitzgibbon J, Paschka P (2010) The clinical relevance of Wilms Tumour 1 (WT1) gene mutations in acute leukaemia. Hematol Oncol 28(1):13–19. doi:10.1002/hon.931

    CAS  PubMed  Google Scholar 

  41. Shichishima T, Okamoto M, Ikeda K, Kaneshige T, Sugiyama H, Terasawa T, Osumi K, Maruyama Y (2002) HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood 100(1):22–28

    Article  CAS  PubMed  Google Scholar 

  42. Lyakisheva A, Felda O, Ganser A, Schmidt RE, Schubert J (2002) Paroxysmal nocturnal hemoglobinuria: Differential gene expression of EGR-1 and TAXREB107. Exp Hematol 30(1):18–25. doi:S0301472X01007639 [pii]

    Google Scholar 

  43. Joslin JM, Fernald AA, Tennant TR, Davis EM, Kogan SC, Anastasi J, Crispino JD, Le Beau MM (2007) Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Blood 110(2):719–726. doi:blood-2007-01-068809 [pii] 10.1182/blood-2007-01-068809

  44. Heeney MM, Ormsbee SM, Moody MA, Howard TA, DeCastro CM, Ware RE (2003) Increased expression of anti-apoptosis genes in peripheral blood cells from patients with paroxysmal nocturnal hemoglobinuria. Mol Genet Metab 78(4):291–294. doi:S1096719203000477 [pii]

    Google Scholar 

  45. Kinoshita T, Inoue N (2002) Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria. Int J Hematol 75(2):117–122

    Article  PubMed  Google Scholar 

  46. Krawitz PM, Hochsmann B, Murakami Y, Teubner B, Kruger U, Klopocki E, Neitzel H, Hoellein A, Schneider C, Parkhomchuk D, Hecht J, Robinson PN, Mundlos S, Kinoshita T, Schrezenmeier H (2013) A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. Blood 122 (7):1312–1315. doi:blood-2013-01-481499 [pii] 10.1182/blood-2013-01-481499

  47. Ohishi K, Inoue N, Maeda Y, Takeda J, Riezman H, Kinoshita T (2000) Gaa1p and gpi8p are components of a glycosylphosphatidylinositol (GPI) transamidase that mediates attachment of GPI to proteins. Mol Biol Cell 11(5):1523–1533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ohishi K, Inoue N, Kinoshita T (2001) PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a complex with GAA1 and GPI8. EMBO J 20(15):4088–4098. doi:10.1093/emboj/20.15.4088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hong Y, Ohishi K, Kang JY, Tanaka S, Inoue N, Nishimura J, Maeda Y, Kinoshita T (2003) Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins. Mol Biol Cell 14(5):1780–1789. doi:10.1091/mbc.E02-12-0794 E02-12-0794 [pii]

  50. Gurvich N, Perna F, Farina A, Voza F, Menendez S, Hurwitz J, Nimer SD (2010) L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability. Proc Natl Acad Sci U S A 107(52):22552–22557. doi: 1017092108 [pii] 10.1073/pnas.1017092108

  51. Perna F, Gurvich N, Hoya-Arias R, Abdel-Wahab O, Levine RL, Asai T, Voza F, Menendez S, Wang L, Liu F, Zhao X, Nimer SD (2010) Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera. Blood 116(15):2812–2821. doi:blood-2010-02-270611 [pii] 10.1182/blood-2010-02-270611

  52. Aziz A, Baxter EJ, Edwards C, Cheong CY, Ito M, Bench A, Kelley R, Silber Y, Beer PA, Chng K, Renfree MB, McEwen K, Gray D, Nangalia J, Mufti GJ, Hellstrom-Lindberg E, Kiladjian JJ, McMullin MF, Campbell PJ, Ferguson-Smith AC, Green AR (2013) Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions. J Clin Invest 123(5):2169–2182. doi: 66113 [pii] 10.1172/JCI66113

  53. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O’Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369(25):2391–2405. doi:10.1056/NEJMoa1312542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, Miyano S, Kojima S, Ito E, Ogawa S (2013) The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet 45(11):1293–1299. doi:ng.2759 [pii] 10.1038/ng.2759

  55. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, Sato-Otsubo A, Sato Y, Liu D, Suzuki H, Wu CO, Shiraishi Y, Clemente MJ, Kataoka K, Shiozawa Y, Okuno Y, Chiba K, Tanaka H, Nagata Y, Katagiri T, Kon A, Sanada M, Scheinberg P, Miyano S, Maciejewski JP, Nakao S, Young NS, Ogawa S (2015) Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 373(1):35–47. doi:10.1056/NEJMoa1414799

    Article  CAS  PubMed  Google Scholar 

  56. Inoue N, Murakami Y, Kinoshita T (2003) Molecular genetics of paroxysmal nocturnal hemoglobinuria. Int J Hematol 77(2):107–112

    Article  CAS  PubMed  Google Scholar 

  57. Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O’Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, DiPersio JF, Ding L, Mardis ER, Wilson RK (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150(2):264–278. doi:S0092-8674(12)00777-5 [pii] 10.1016/j.cell.2012.06.023

  58. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, Schmidt HK, Yellapantula V, Miller CA, Ozenberger BA, Welch JS, Link DC, Walter MJ, Mardis ER, Dipersio JF, Chen F, Wilson RK, Ley TJ, Ding L (2014) Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20(12):1472–1478. doi: nm.3733 [pii] 10.1038/nm.3733

  59. Chotirat S, Thongnoppakhun W, Wanachiwanawin W, Auewarakul CU (2015) Acquired somatic mutations of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) in preleukemic disorders. Blood Cells Mol Dis 54(3):286–291. doi:S1079-9796(14)00150-8 [pii] 10.1016/j.bcmd.2014.11.017

  60. Mortazavi Y, Tooze JA, Gordon-Smith EC, Rutherford TR (2000) N-RAS gene mutation in patients with aplastic anemia and aplastic anemia/ paroxysmal nocturnal hemoglobinuria during evolution to clonal disease. Blood 95(2):646–650

    CAS  PubMed  Google Scholar 

  61. Ortmann CA, Kent DG, Nangalia J, Silber Y, Wedge DC, Grinfeld J, Baxter EJ, Massie CE, Papaemmanuil E, Menon S, Godfrey AL, Dimitropoulou D, Guglielmelli P, Bellosillo B, Besses C, Dohner K, Harrison CN, Vassiliou GS, Vannucchi A, Campbell PJ, Green AR (2015) Effect of mutation order on myeloproliferative neoplasms. N Engl J Med 372(7):601–612. doi:10.1056/NEJMoa1412098

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Tumor Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higahsinari-ku, 537-8511, Osaka, Japan

    Norimitsu Inoue

  2. Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Taroh Kinoshita

  3. WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Taroh Kinoshita

Authors
  1. Norimitsu Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taroh Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norimitsu Inoue .

Editor information

Editors and Affiliations

  1. Department of Hematology and Ocology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Yuzuru Kanakura

  2. Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan

    Taroh Kinoshita

  3. Dept of Hematology and Ocology, Osaka University Dept of Hematology and Ocology, Suita, Osaka, Japan

    Jun-ichi Nishimura

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Japan KK

About this chapter

Cite this chapter

Inoue, N., Kinoshita, T. (2017). Pathogenesis of Clonal Dominance in PNH: Growth Advantage in PNH. In: Kanakura, Y., Kinoshita, T., Nishimura, Ji. (eds) Paroxysmal Nocturnal Hemoglobinuria. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56003-6_14

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-56003-6_14

  • Published:

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-56001-2

  • Online ISBN: 978-4-431-56003-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation