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Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia

Leukemia volume 29, pages 1243–1252 (2015)Cite this article

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Abstract

Genetic abnormalities are a hallmark of cancer. Hereby, cytogenetic aberrations and small-scale abnormalities, such as single-nucleotide variations and insertion/deletion mutations, have emerged as two alternative modes of genetic diversification. Both mechanisms are at work in acute myeloid leukemia (AML), in which conventional karyotyping and molecular studies demonstrate that gene mutations occur predominantly in cytogenetically normal AML, whereas chromosomal changes are a driving force of development and progression of disease in aberrant karyotype AML. All steps of disease evolution in AML, ranging from the transformation of preleukemic clones into overt leukemia to the expansion and recurrence of malignant clones, are paralleled by clonal evolution at either the gene mutation or chromosome aberration level. Preleukemic conditions, such as Fanconi anemia and Bloom syndrome, demonstrate that the acquisition of chromosomal aberrations can contribute to leukemic transformation. Similar to what has been shown at the mutational level, expansion and recurrence of AML clones goes along with increasing genetic diversification. Hereby, cytogenetically more evolved subclones are at a proliferative advantage and outgrow ancestor clones or have evolved toward a more aggressive behavior with additional newly acquired aberrations as compared with the initial leukemic clone, respectively.

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References

  1. Jacobs PA, Court Brown WM, Doll R . Distribution of human chromosome counts in relation to age. Nature 1961; 191: 1178–1180.

    CAS  PubMed  Google Scholar 

  2. Jacobs PA, Brunton M, Court Brown WM, Doll R, Goldstein H . Change of human chromosome count distribution with age: evidence for a sex differences. Nature 1963; 197: 1080–1081.

    CAS  PubMed  Google Scholar 

  3. Galloway SM, Buckton KE . Aneuploidy and ageing: chromosome studies on a random sample of the population using G-banding. Cytogenet Cell Genet 1978; 20: 78–95.

    CAS  PubMed  Google Scholar 

  4. Pierre RV, Hoagland HC . Age-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging. Cancer 1972; 30: 889–894.

    CAS  PubMed  Google Scholar 

  5. Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 2000; 27: 11–16.

    CAS  PubMed  Google Scholar 

  6. Loss of the Y chromosome from normal and neoplastic bone marrows. United Kingdom Cancer Cytogenetics Group (UKCCG). Genes Chromosomes Cancer 1992; 5: 83–88.

    Google Scholar 

  7. Forsberg LA, Rasi C, Malmqvist N, Davies H, Pasupulati S, Pakalapati G et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat Genet 2014; 46: 624–628.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 2012; 44: 642–650.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet 2012; 44: 651–658.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Frohling S, Dohner H . Chromosomal abnormalities in cancer. N Engl J Med 2008; 359: 722–734.

    Article  CAS  PubMed  Google Scholar 

  11. Lengauer C, Kinzler KW, Vogelstein B . Genetic instability in colorectal cancers. Nature 1997; 386: 623–627.

    CAS  PubMed  Google Scholar 

  12. Walther A, Houlston R, Tomlinson I . Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut 2008; 57: 941–950.

    CAS  PubMed  Google Scholar 

  13. White BS, DiPersio JF . Genomic tools in acute myeloid leukemia: From the bench to the bedside. Cancer 2014; 120: 1134–1144.

    PubMed  Google Scholar 

  14. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C . Emerging landscape of oncogenic signatures across human cancers. Nat Genet 2013; 45: 1127–1133.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 2011; 333: 1039–1043.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sheltzer JM, Blank HM, Pfau SJ, Tange Y, George BM, Humpton TJ et al. Aneuploidy drives genomic instability in yeast. Science 2011; 333: 1026–1030.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kolodner RD, Cleveland DW, Putnam CD . Cancer. Aneuploidy drives a mutator phenotype in cancer. Science 2011; 333: 942–943.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 2013; 155: 948–962.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Google Scholar 

  20. Loeb LA, Springgate CF, Battula N . Errors in DNA replication as a basis of malignant changes. Cancer Res 1974; 34: 2311–2321.

    CAS  PubMed  Google Scholar 

  21. Loeb LA . Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 1991; 51: 3075–3079.

    CAS  PubMed  Google Scholar 

  22. Araten DJ, Golde DW, Zhang RH, Thaler HT, Gargiulo L, Notaro R et al. A quantitative measurement of the human somatic mutation rate. Cancer Res 2005; 65: 8111–8117.

    CAS  PubMed  Google Scholar 

  23. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415–421.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bakhoum SF, Compton DA . Chromosomal instability and cancer: a complex relationship with therapeutic potential. J Clin Invest 2012; 122: 1138–1143.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Janssen A, van der Burg M, Szuhai K, Kops GJ, Medema RH . Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 2011; 333: 1895–1898.

    Article  CAS  PubMed  Google Scholar 

  26. Hunter A . High risk of malignancy in mosaic variegated aneuploidy syndrome. Am J Med Genet A 2003; 117A: 199.

    PubMed  Google Scholar 

  27. Jacquemont S, Boceno M, Rival JM, Mechinaud F, David A . High risk of malignancy in mosaic variegated aneuploidy syndrome. Am J Med Genet 2002; 109: 17–21, discussion 16.

    PubMed  Google Scholar 

  28. Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 2004; 36: 1159–1161.

    CAS  PubMed  Google Scholar 

  29. Rio Frio T, Lavoie J, Hamel N, Geyer FC, Kushner YB, Novak DJ et al. Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia. N Engl J Med 2010; 363: 2628–2637.

    PubMed  Google Scholar 

  30. Nasmyth K . Segregating sister genomes: the molecular biology of chromosome separation. Science 2002; 297: 559–565.

    CAS  PubMed  Google Scholar 

  31. Schockel L, Mockel M, Mayer B, Boos D, Stemmann O . Cleavage of cohesin rings coordinates the separation of centrioles and chromatids. Nat Cell Biol 2011; 13: 966–972.

    PubMed  Google Scholar 

  32. Tsou MF, Wang WJ, George KA, Uryu K, Stearns T, Jallepalli PV . Polo kinase and separase regulate the mitotic licensing of centriole duplication in human cells. Dev Cell 2009; 17: 344–354.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481: 506–510.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med 2012; 366: 1090–1098.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150: 264–278.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet 2013; 45: 1232–1237.

    CAS  PubMed  Google Scholar 

  37. Thol F, Bollin R, Gehlhaar M, Walter C, Dugas M, Suchanek KJ et al. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood 2014; 123: 914–920.

    CAS  PubMed  Google Scholar 

  38. Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet 2013; 45: 1293–1299.

    CAS  PubMed  Google Scholar 

  39. Thota S, Viny AD, Makishima H, Spitzer B, Radivoyevitch T, Przychodzen B et al. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood 2014; 124: 1790–1798.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.

    PubMed  Google Scholar 

  41. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.

    CAS  PubMed  Google Scholar 

  42. Mrozek K . Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. Semin Oncol 2008; 35: 365–377.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Heilig CE, Loffler H, Mahlknecht U, Janssen JW, Ho AD, Jauch A et al. Chromosomal instability correlates with poor outcome in patients with myelodysplastic syndromes irrespectively of the cytogenetic risk group. J Cell Mol Med 2010; 14: 895–902.

    PubMed  Google Scholar 

  44. D'Andrea AD, Grompe M . The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 2003; 3: 23–34.

    CAS  PubMed  Google Scholar 

  45. Naim V, Rosselli F . The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat Cell Biol 2009; 11: 761–768.

    CAS  PubMed  Google Scholar 

  46. Meyer S, Neitzel H, Tonnies H . Chromosomal aberrations associated with clonal evolution and leukemic transformation in fanconi anemia: clinical and biological implications. Anemia 2012; 2012: 349837.

    PubMed  PubMed Central  Google Scholar 

  47. Rosenberg PS, Greene MH, Alter BP . Cancer incidence in persons with Fanconi anemia. Blood 2003; 101: 822–826.

    CAS  PubMed  Google Scholar 

  48. Quentin S, Cuccuini W, Ceccaldi R, Nibourel O, Pondarre C, Pages MP et al. Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions. Blood 2011; 117: e161–e170.

    CAS  PubMed  Google Scholar 

  49. Mehta PA, Harris RE, Davies SM, Kim MO, Mueller R, Lampkin B et al. Numerical chromosomal changes and risk of development of myelodysplastic syndrome—acute myeloid leukemia in patients with Fanconi anemia. Cancer Genet Cytogenet 2010; 203: 180–186.

    CAS  PubMed  Google Scholar 

  50. Poppe B, Van Limbergen H, Van Roy N, Vandecruys E, De Paepe A, Benoit Y et al. Chromosomal aberrations in Bloom syndrome patients with myeloid malignancies. Cancer Genet Cytogenet 2001; 128: 39–42.

    CAS  PubMed  Google Scholar 

  51. Li Y, Li X, Ge M, Shi J, Qian L, Zheng Y et al. Long-term follow-up of clonal evolutions in 802 aplastic anemia patients: a single-center experience. Ann Hematol 2011; 90: 529–537.

    PubMed  Google Scholar 

  52. Afable MG 2nd, Tiu RV, Maciejewski JP . Clonal evolution in aplastic anemia. Hematology Am Soc Hematol Educ Program 2011; 2011: 90–95.

    PubMed  Google Scholar 

  53. Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS . Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 2002; 99: 3129–3135.

    CAS  PubMed  Google Scholar 

  54. Ohara A, Kojima S, Hamajima N, Tsuchida M, Imashuku S, Ohta S et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997; 90: 1009–1013.

    CAS  PubMed  Google Scholar 

  55. Scheinberg P, Cooper JN, Sloand EM, Wu CO, Calado RT, Young NS . Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 2010; 304: 1358–1364.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Dumitriu B, Feng X, Ueda Y, Kajigaya S, Townsley D, Zsu J et al. Clonal Evolution In Aplastic Anemia Is Driven By Chromosomal Instability Rather Than Mutations In Myeloid Malignancy Candidate Gene. 55th ASH Annual Meeting and Exposition, plenary session 2013.

  57. Lange K, Holm L, Vang Nielsen K, Hahn A, Hofmann W, Kreipe H et al. Telomere shortening and chromosomal instability in myelodysplastic syndromes. Genes Chromosomes Cancer 2010; 49: 260–269.

    CAS  PubMed  Google Scholar 

  58. Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc Natl Acad Sci USA 2009; 106: 1187–1192.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. McClintock B . The Stability of Broken Ends of Chromosomes in Zea Mays. Genetics 1941; 26: 234–282.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. DePinho RA . The age of cancer. Nature 2000; 408: 248–254.

    CAS  PubMed  Google Scholar 

  61. Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood 2002; 99: 3801–3805.

    CAS  PubMed  Google Scholar 

  62. Stark B, Jeison M, Preudhomme C, Fenaux P, Ash S, Korek Y et al. Acquired trisomy 21 and distinct clonal evolution in acute megakaryoblastic leukaemia in young monozygotic twins. Br J Haematol 2002; 118: 1082–1086.

    CAS  PubMed  Google Scholar 

  63. Bateman CM, Colman SM, Chaplin T, Young BD, Eden TO, Bhakta M et al. Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 2010; 115: 3553–3558.

    CAS  PubMed  Google Scholar 

  64. Kwong YL, Wong KF, Chan V, Chan CH . Persistence of AML1 rearrangement in peripheral blood cells in t(8;21). Cancer Genet Cytogenet 1996; 88: 151–154.

    CAS  PubMed  Google Scholar 

  65. Miyamoto T, Nagafuji K, Akashi K, Harada M, Kyo T, Akashi T et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood 1996; 87: 4789–4796.

    CAS  PubMed  Google Scholar 

  66. Miyamoto T, Weissman IL, Akashi K . AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci USA 2000; 97: 7521–7526.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Feuring-Buske M, Haase D, Buske C, Hiddemann W, Wormann B . Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission. Leukemia 1999; 13: 386–392.

    CAS  PubMed  Google Scholar 

  68. Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R . Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA 2014; 111: 2548–2553.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Greaves M . Darwin and evolutionary tales in leukemia. The Ham-Wasserman Lecture. Hematology Am Soc Hematol Educ Program 2009, 3–12.

    Google Scholar 

  70. Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011; 469: 356–361.

    CAS  PubMed  Google Scholar 

  71. Greaves M, Maley CC . Clonal evolution in cancer. Nature 2012; 481: 306–313.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144: 27–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Rausch T, Jones DT, Zapatka M, Stutz AM, Zichner T, Weischenfeldt J et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012; 148: 59–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bernasconi P, Klersy C, Boni M, Cavigliano PM, Giardini I, Rocca B et al. Does cytogenetic evolution have any prognostic relevance in myelodysplastic syndromes? A study on 153 patients from a single institution. Ann Hematol 2010; 89: 545–551.

    PubMed  Google Scholar 

  75. Wang H, Wang XQ, Xu XP, Lin GW . Cytogenetic evolution correlates with poor prognosis in myelodysplastic syndrome. Cancer Genet Cytogenet 2010; 196: 159–166.

    CAS  PubMed  Google Scholar 

  76. Cordoba I, Gonzalez-Porras JR, Nomdedeu B, Luno E, de Paz R, Such E et al. Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome. Cancer 2012; 118: 127–133.

    CAS  PubMed  Google Scholar 

  77. Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol 2012; 30: 820–829.

    PubMed  PubMed Central  Google Scholar 

  78. Shirneshan K, Platzbecker U, Nolte F, Giagounidis A, Götze K, Schlenk RF et al. Monitoring By Chromosome Banding Analysis (CBA) and FISH Of Circulating CD34+ Cells In Low-Risk MDS Patients Treated In The Le-Mon-5 Study With Lenalidomide Monotherapy Reveals 82% Cytogenetic Responders With Different Response –, Evolutionary -, and Remission Patterns and No Increased Karyotype Evolution (KE). 55th ASH Annual Meeting and Exposition, plenary session 2013.

  79. Bershteyn M, Hayashi Y, Desachy G, Hsiao EC, Sami S, Tsang KM et al. Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells. Nature 2014; 507: 99–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  81. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.

    CAS  PubMed  Google Scholar 

  82. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325–4336.

    CAS  PubMed  Google Scholar 

  83. Schlenk RF, Benner A, Krauter J, Buchner T, Sauerland C, Ehninger G et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004; 22: 3741–3750.

    CAS  PubMed  Google Scholar 

  84. Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008; 26: 4791–4797.

    PubMed  Google Scholar 

  85. Rucker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119: 2114–2121.

    PubMed  Google Scholar 

  86. Middeke JM, Fang M, Cornelissen JJ, Mohr B, Appelbaum FR, Stadler M et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood 2014; 123: 2960–2967.

    CAS  PubMed  Google Scholar 

  87. Bochtler T, Stolzel F, Heilig CE, Kunz C, Mohr B, Jauch A et al. Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia. J Clin Oncol 2013; 31: 3898–3905.

    PubMed  Google Scholar 

  88. Sawyer JR, Roloson GJ, Head DR, Becton D . Karyotype evolution in a patient with Down syndrome and acute leukemia following a congenital leukemoid reaction. Med Pediatr Oncol 1994; 22: 404–409.

    CAS  PubMed  Google Scholar 

  89. Landau DA, Carter SL, Getz G, Wu CJ . Clonal evolution in hematological malignancies and therapeutic implications. Leukemia 2014; 28: 34–43.

    CAS  PubMed  Google Scholar 

  90. Delaunay J, Vey N, Leblanc T, Fenaux P, Rigal-Huguet F, Witz F et al. Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood 2003; 102: 462–469.

    CAS  PubMed  Google Scholar 

  91. Perrot A, Luquet I, Pigneux A, Mugneret F, Delaunay J, Harousseau JL et al. Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood 2011; 118: 679–685.

    CAS  PubMed  Google Scholar 

  92. Volkert S, Kohlmann A, Schnittger S, Kern W, Haferlach T, Haferlach C . Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome. Genes Chromosomes Cancer 2014; 53: 402–410.

    CAS  PubMed  Google Scholar 

  93. Paulsson K . Genomic heterogeneity in acute leukemia. Cytogenet Genome Res 2013; 139: 174–180.

    CAS  PubMed  Google Scholar 

  94. Kronke J, Bullinger L, Teleanu V, Tschurtz F, Gaidzik VI, Kuhn MW et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 2013; 122: 100–108.

    PubMed  Google Scholar 

  95. Bacher U, Haferlach T, Alpermann T, Zenger M, Kroger N, Beelen DW et al. Comparison of cytogenetic clonal evolution patterns following allogeneic hematopoietic transplantation versus conventional treatment in patients at relapse of AML. Biol Blood Marrow Transplant 2010; 16: 1649–1657.

    PubMed  Google Scholar 

  96. Garson OM, Hagemeijer A, Sakurai M, Reeves BR, Swansbury GJ, Williams GJ et al. Cytogenetic studies of 103 patients with acute myelogenous leukemia in relapse. Cancer Genet Cytogenet 1989; 40: 187–202.

    CAS  PubMed  Google Scholar 

  97. Schmidt-Hieber M, Blau IW, Richter G, Turkmen S, Bommer C, Thiel G et al. Cytogenetic studies in acute leukemia patients relapsing after allogeneic stem cell transplantation. Cancer Genet Cytogenet 2010; 198: 135–143.

    CAS  PubMed  Google Scholar 

  98. Ottone T, Zaza S, Divona M, Hasan SK, Lavorgna S, Laterza S et al. Identification of emerging FLT3 ITD-positive clones during clinical remission and kinetics of disease relapse in acute myeloid leukaemia with mutated nucleophosmin. Br J Haematol 2013; 161: 533–540.

    CAS  PubMed  Google Scholar 

  99. Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 2012; 4: 149ra18.

    Google Scholar 

  100. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377–1380.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328–333.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Damm F, Markus B, Thol F, Morgan M, Gohring G, Schlegelberger B et al. TET2 mutations in cytogenetically normal acute myeloid leukemia: Clinical implications and evolutionary patterns. Genes Chromosomes Cancer 2014; 53: 824–832.

    CAS  PubMed  Google Scholar 

  103. Nazha A, Cortes J, Faderl S, Pierce S, Daver N, Kadia T et al. Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete response and relapse in patients with acute myeloid leukemia. Haematologica 2012; 97: 1242–1245.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Gilliland DG . Molecular genetics of human leukemias: new insights into therapy. Semin Hematol 2002; 39 (4 Suppl 3): 6–11.

    CAS  PubMed  Google Scholar 

  105. Frohling S, Scholl C, Gilliland DG, Levine RL . Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 2005; 23: 6285–6295.

    CAS  PubMed  Google Scholar 

  106. Scholl C, Gilliland DG, Frohling S . Deregulation of signaling pathways in acute myeloid leukemia. Semin Oncol 2008; 35: 336–345.

    CAS  PubMed  Google Scholar 

  107. Grove CS, Vassiliou GS . Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis Model Mech 2014; 7: 941–951.

    PubMed  PubMed Central  Google Scholar 

  108. Parkin B, Ouillette P, Li Y, Keller J, Lam C, Roulston D et al. Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia. Blood 2013; 121: 369–377.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Chen SJ, Shen Y, Chen Z . A panoramic view of acute myeloid leukemia. Nat Genet 2013; 45: 586–587.

    CAS  PubMed  Google Scholar 

  110. Gohring G, Giagounidis A, Busche G, Kreipe HH, Zimmermann M, Hellstrom-Lindberg E et al. Patients with del(5q) MDS who fail to achieve sustained erythroid or cytogenetic remission after treatment with lenalidomide have an increased risk for clonal evolution and AML progression. Ann Hematol 2010; 89: 365–374.

    PubMed  Google Scholar 

  111. Jadersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Gohring G et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 2011; 29: 1971–1979.

    PubMed  Google Scholar 

  112. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol 2001; 19: 1405–1413.

    CAS  PubMed  Google Scholar 

  113. Wong TN, Ramsingh G, Young A, Shen D, Miller C, Lamprecht T et al. The role of early TP53 mutations on the evolution of therapy-related AML. 55th ASH Annual Meeting and Exposition, plenary session 2013.

  114. Anderhub SJ, Kramer A, Maier B . Centrosome amplification in tumorigenesis. Cancer Lett 2012; 322: 8–17.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    T Bochtler & A Krämer

  2. German Cancer Research Center (DKFZ) and Department of Internal Medicine V, Clinical Cooperation Unit Molecular Hematology/Oncology, University of Heidelberg, Heidelberg, Germany

    T Bochtler & A Krämer

  3. Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    S Fröhling

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  1. T Bochtler
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  2. S Fröhling
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  3. A Krämer
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Correspondence to A Krämer.

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Bochtler, T., Fröhling, S. & Krämer, A. Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia. Leukemia 29, 1243–1252 (2015). https://doi.org/10.1038/leu.2015.32

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  • DOI: https://doi.org/10.1038/leu.2015.32

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