Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Clonal evolution in hematological malignancies and therapeutic implications

Leukemia volume 28, pages 34–43 (2014)Cite this article

Subjects

Abstract

The ability of cancer to evolve and adapt is a principal challenge to therapy in general and to the paradigm of targeted therapy in particular. This ability is fueled by the co-existence of multiple, genetically heterogeneous subpopulations within the cancer cell population. Increasing evidence has supported the idea that these subpopulations are selected in a Darwinian fashion, by which the genetic landscape of the tumor is continuously reshaped. Massively parallel sequencing has enabled a recent surge in our ability to study this process, adding to previous efforts using cytogenetic methods and targeted sequencing. Altogether, these studies reveal the complex evolutionary trajectories occurring across individual hematological malignancies. They also suggest that while clonal evolution may contribute to resistance to therapy, treatment may also hasten the evolutionary process. New insights into this process challenge us to understand the impact of treatment on clonal evolution and inspire the development of novel prognostic and therapeutic strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037.

    CAS  PubMed  Google Scholar 

  2. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013; 369: 111–121.

    CAS  PubMed  Google Scholar 

  3. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139.

    CAS  PubMed  Google Scholar 

  4. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Arkenau HT, Kefford R, Long GV . Targeting BRAF for patients with melanoma. Br J Cancer 2011; 104: 392–398.

    CAS  PubMed  Google Scholar 

  6. Westbrook CA, Hooberman AL, Spino C, Dodge RK, Larson RA, Davey F et al. Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762). Blood 1992; 80: 2983–2990.

    CAS  PubMed  Google Scholar 

  7. Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990; 247: 1079–1082.

    CAS  PubMed  Google Scholar 

  8. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–1042.

    CAS  PubMed  Google Scholar 

  9. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002; 100: 1965–1971.

    CAS  PubMed  Google Scholar 

  10. Foa R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2011; 118: 6521–6528.

    CAS  PubMed  Google Scholar 

  11. 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 

  12. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    CAS  PubMed  Google Scholar 

  13. Waanders E, Scheijen B, van der Meer LT, van Reijmersdal SV, van Emst L, Kroeze Y et al. The origin and nature of tightly clustered BTG1 deletions in precursor B-cell acute lymphoblastic leukemia support a model of multiclonal evolution. PLoS Genet 2012; 8: e1002533.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Merlo LM, Pepper JW, Reid BJ, Maley CC . Cancer as an evolutionary and ecological process. Nat Rev Cancer 2006; 6: 924–935.

    CAS  PubMed  Google Scholar 

  15. Harris JF, Chambers AF, Hill RP, Ling V . Metastatic variants are generated spontaneously at a high rate in mouse KHT tumor. Proc Natl Acad Sci USA 1982; 79: 5547–5551.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cillo C, Dick JE, Ling V, Hill RP . Generation of drug-resistant variants in metastatic B16 mouse melanoma cell lines. Cancer Res 1987; 47: 2604–2608.

    CAS  PubMed  Google Scholar 

  17. Fearon ER, Vogelstein B . A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759–767.

    CAS  PubMed  Google Scholar 

  18. Zhang L, Znoyko I, Costa LJ, Conlin LK, Daber RD, Self SE et al. Clonal diversity analysis using SNP microarray: a new prognostic tool for chronic lymphocytic leukemia. Cancer Genet 2011; 204: 654–665.

    CAS  PubMed  Google Scholar 

  19. Calissano C, Damle R, Hayes G, Murphy E, Hellerstein M, Moreno C et al. In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia. Blood 2009; 114: 4832–4842.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bagnara D, Callea V, Stelitano C, Morabito F, Fabris S, Neri A et al. IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia. Br J Haematol 2006; 133: 50–58.

    CAS  PubMed  Google Scholar 

  21. Stilgenbauer S, Sander S, Bullinger L, Benner A, Leupolt E, Winkler D et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica 2007; 92: 1242–1245.

    PubMed  Google Scholar 

  22. Gunnarsson R, Mansouri L, Isaksson A, Goransson H, Cahill N, Jansson M et al. Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia. Haematologica 2011; 96: 1161–1169.

    PubMed  PubMed Central  Google Scholar 

  23. Nowell PC . The clonal evolution of tumor cell populations. Science 1976; 194: 23–28.

    CAS  PubMed  Google Scholar 

  24. Fidler IJ . Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 1978; 38: 2651–2660.

    CAS  PubMed  Google Scholar 

  25. Cairo MS, Jordan CT, Maley CC, Chao C, Melnick A, Armstrong SA et al. NCI first International Workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: report from the committee on the biological considerations of hematological relapse following allogeneic stem cell transplantation unrelated to graft-versus-tumor effects: state of the science. Biol Blood Marrow Transplant 2010; 16: 709–728.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Loeb LA . Human cancers express mutator phenotypes: origin, consequences and targeting. Nat Rev Cancer 2011; 11: 450–457.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bassaganyas L, Bea S, Escaramis G, Tornador C, Salaverria I, Zapata L et al. Sporadic and reversible chromothripsis in chronic lymphocytic leukemia revealed by longitudinal genomic analysis. Leukemia, 2013; E-publication: 2013/04/25.

  28. Bouwman P, Jonkers J . The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer 2012; 12: 587–598.

    CAS  PubMed  Google Scholar 

  29. Schwartz M, Zlotorynski E, Kerem B . The molecular basis of common and rare fragile sites. Cancer Lett 2006; 232: 13–26.

    CAS  PubMed  Google Scholar 

  30. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499: 214–218.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gawad C, Pepin F, Carlton VE, Klinger M, Logan AC, Miklos DB et al. Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia. Blood 2012; 120: 4407–4417.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mahowald GK, Baron JM, Sleckman BP . Collateral damage from antigen receptor gene diversification. Cell 2008; 135: 1009–1012.

    CAS  PubMed  Google Scholar 

  33. Meyerson M, Gabriel S, Getz G . Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 2010; 11: 685–696.

    CAS  PubMed  Google Scholar 

  34. Pleasance E, Cheetham R, Stephens P, McBride D, Humphray S, Greenman C et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010; 463: 191–196.

    CAS  PubMed  Google Scholar 

  35. Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R et al. A census of human cancer genes. Nat Rev Cancer 2004; 4: 177–183.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–892.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 2012; 30: 413–421.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW et al. The life history of 21 breast cancers. Cell 2012; 149: 994–1007.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 

  40. Landau D, Carter S, Stojanov P, McKenna A, Stevenson K, Lawrence M et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152: 714–726.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012; 486: 395–399.

    CAS  PubMed  Google Scholar 

  43. Maley CC, Galipeau PC, Li X, Sanchez CA, Paulson TG, Reid BJ . Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus. Cancer Res 2004; 64: 3414–3427.

    CAS  PubMed  Google Scholar 

  44. Bozic I, Antal T, Ohtsuki H, Carter H, Kim D, Chen S et al. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci USA 2010; 107: 18545–18550.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 

  46. 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 

  47. Egan JB, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 2012; 120: 1060–1066.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012; 120: 1067–1076.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011; 20: 810–817.

    CAS  PubMed  Google Scholar 

  50. Ene CI, Fine HA . Many tumors in one: a daunting therapeutic prospect. Cancer Cell 2011; 20: 695–697.

    CAS  PubMed  Google Scholar 

  51. Quentmeier H, Amini RM, Berglund M, Dirks WG, Ehrentraut S, Geffers R et al. U-2932: two clones in one cell line, a tool for the study of clonal evolution. Leukemia 2013; 27: 1155–1164.

    CAS  PubMed  Google Scholar 

  52. Campbell PJ, Pleasance ED, Stephens PJ, Dicks E, Rance R, Goodhead I et al. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc Natl Acad Sci USA 2008; 105: 13081–13086.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Gaken J, Lea NC et al. Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood 2010; 116: 3923–3932.

    CAS  PubMed  Google Scholar 

  54. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J et al. Tumour evolution inferred by single-cell sequencing. Nature 2011; 472: 90–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Smith ZD, Meissner A . DNA methylation: roles in mammalian development. Nat Rev Genet 2013; 14: 204–220.

    CAS  PubMed  Google Scholar 

  56. Siegmund KD, Marjoram P, Woo YJ, Tavare S, Shibata D . Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers. Proc Natl Acad Sci USA 2009; 106: 4828–4833.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. De S, Shaknovich R, Riester M, Elemento O, Geng H, Kormaksson M et al. Aberration in DNA methylation in B-cell lymphomas has a complex origin and increases with disease severity. PLoS Genet 2013; 9: e1003137.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 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 

  59. Clappier E, Gerby B, Sigaux F, Delord M, Touzri F, Hernandez L et al. Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse. J Exp Med 2011; 208: 653–661.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Piccirillo SG, Combi R, Cajola L, Patrizi A, Redaelli S, Bentivegna A et al. Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene 2009; 28: 1807–1811.

    CAS  PubMed  Google Scholar 

  61. Kreso A, O'Brien CA, van Galen P, Gan OI, Notta F, Brown AM et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 2013; 339: 543–548.

    CAS  PubMed  Google Scholar 

  62. Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK . Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 2009; 459: 428–432.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Greaves M . Cancer stem cells: back to Darwin? Semin Cancer Biol 2010; 20: 65–70.

    PubMed  Google Scholar 

  64. Arias AM, Hayward P . Filtering transcriptional noise during development: concepts and mechanisms. Nat Rev Genet 2006; 7: 34–44.

    CAS  PubMed  Google Scholar 

  65. Balazsi G, van Oudenaarden A, Collins JJ . Cellular decision making and biological noise: from microbes to mammals. Cell 2011; 144: 910–925.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gupta PB, Chaffer CL, Weinberg RA . Cancer stem cells: mirage or reality? Nat Med 2009; 15: 1010–1012.

    CAS  PubMed  Google Scholar 

  67. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.

    CAS  PubMed  Google Scholar 

  68. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009; 138: 645–659.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Mizuno H, Spike BT, Wahl GM, Levine AJ . Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures. Proc Natl Acad Sci USA 2010; 107: 22745–22750.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 2009; 138: 1083–1095.

    CAS  PubMed  Google Scholar 

  71. Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 2004; 6: 587–596.

    CAS  PubMed  Google Scholar 

  72. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ . Efficient tumour formation by single human melanoma cells. Nature 2008; 456: 593–598.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 2010; 140: 62–73.

    CAS  PubMed  Google Scholar 

  74. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007; 109: 944–950.

    CAS  PubMed  Google Scholar 

  75. Parsons D, Jones S, Zhang X, Lin J, Leary R, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–1812.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Schuh A, Becq J, Humphray S, Alexa A, Burns A, Clifford R et al. Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns. Blood 2012; 120: 4191–4196.

    CAS  PubMed  Google Scholar 

  77. Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365: 2497–2506.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008; 359: 366–377.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 2008; 451: 1111–1115.

    CAS  PubMed  Google Scholar 

  81. Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006; 66: 7854–7858.

    CAS  PubMed  Google Scholar 

  82. Clevers H . The cancer stem cell: premises, promises and challenges. Nat Med 2011; 17: 313–319.

    CAS  PubMed  Google Scholar 

  83. Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL et al. MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 2009; 15: 4622–4629.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117–125.

    CAS  PubMed  Google Scholar 

  85. Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Lai JL, Philippe N, Facon T et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 2002; 100: 1014–1018.

    CAS  PubMed  Google Scholar 

  86. Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med 2013; 19: 368–371.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Wu CJ . CLL clonal heterogeneity: an ecology of competing subpopulations. Blood 2012; 120: 4117–4118.

    CAS  PubMed  Google Scholar 

  88. Morgan GJ, Walker BA, Davies FE . The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12: 335–348.

    CAS  PubMed  Google Scholar 

  89. Jablonski D . Lessons from the past: evolutionary impacts of mass extinctions. Proc Natl Acad Sci USA 2001; 98: 5393–5398.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Nowak MA, Sigmund K . Evolutionary dynamics of biological games. Science 2004; 303: 793–799.

    CAS  PubMed  Google Scholar 

  91. Vincent TL, Gatenby RA . An evolutionary model for initiation, promotion, and progression in carcinogenesis. Int J Oncol 2008; 32: 729–737.

    CAS  PubMed  Google Scholar 

  92. Maley CC, Galipeau PC, Finley JC, Wongsurawat VJ, Li X, Sanchez CA et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet 2006; 38: 468–473.

    CAS  PubMed  Google Scholar 

  93. CLL Trialists Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Cancer Inst 1999; 91: 861–868.

    Google Scholar 

  94. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F . The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood 2009; 114: 3367–3375.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    PubMed  Google Scholar 

  97. Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013; 121: 1403–1412.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol 2009; 27: 4585–4590.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Swanton C . Intratumor heterogeneity: evolution through space and time. Cancer Res 2012; 72: 4875–4882.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  101. Pardanani A, Tefferi A . Imatinib therapy for hypereosinophilic syndrome and eosinophilia-associated myeloproliferative disorders. Leuk Res 2004; 28 (Suppl 1): S47–S52.

    CAS  PubMed  Google Scholar 

  102. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123–134.

    CAS  PubMed  Google Scholar 

  103. Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008; 26: 4268–4275.

    CAS  PubMed  Google Scholar 

  104. Yang H, Higgins B, Kolinsky K, Packman K, Bradley WD, Lee RJ et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res 2012; 72: 779–789.

    CAS  PubMed  Google Scholar 

  105. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88: 593–602.

    CAS  PubMed  Google Scholar 

  106. Bissonnette RP, Echeverri F, Mahboubi A, Green DR . Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 1992; 359: 552–554.

    CAS  PubMed  Google Scholar 

  107. Inda MM, Bonavia R, Mukasa A, Narita Y, Sah DW, Vandenberg S et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev 2010; 24: 1731–1745.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Gillies RJ, Verduzco D, Gatenby RA . Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer 2012; 12: 487–493.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Merlo LM, Maley CC . The role of genetic diversity in cancer. J Clin Invest 2010; 120: 401–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Gatenby RA, Silva AS, Gillies RJ, Frieden BR . Adaptive therapy. Cancer Res 2009; 69: 4894–4903.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Waterhouse M, Pfeifer D, Pantic M, Emmerich F, Bertz H, Finke J . Genome-wide profiling in AML patients relapsing after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2011; 17: 1450–1459, e1.

    CAS  PubMed  Google Scholar 

  112. Stolzel F, Hackmann K, Kuithan F, Mohr B, Fussel M, Oelschlagel U et al. Clonal evolution including partial loss of human leukocyte antigen genes favoring extramedullary acute myeloid leukemia relapse after matched related allogeneic hematopoietic stem cell transplantation. Transplantation 2012; 93: 744–749.

    PubMed  Google Scholar 

  113. 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 

  114. Puente XS, Lopez-Otin C . The evolutionary biography of chronic lymphocytic leukemia. Nat Genet 2013; 45: 229–231.

    CAS  PubMed  Google Scholar 

  115. Hou Y, Song L, Zhu P, Zhang B, Tao Y, Xu X et al. Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm. Cell 2012; 148: 873–885.

    CAS  PubMed  Google Scholar 

  116. Xu X, Hou Y, Yin X, Bao L, Tang A, Song L et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 2012; 148: 886–895.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Shalek AK, Satija R, Adiconis X, Gertner RS, Gaublomme JT, Raychowdhury R et al. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 2013; 498: 236–240.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Weston-Bell N, Gibson J, John M, Ennis S, Pfeifer S, Cezard T et al. Exome sequencing in tracking clonal evolution in multiple myeloma following therapy. Leukemia 2013; 27: 1188–1191.

    CAS  PubMed  Google Scholar 

  119. Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 2013; 121: 1604–1611.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

DAL acknowledges support by the American Society of Hematology (Research Award for Fellows-in-Training), and the American Cancer Society. CJW acknowledges support from the Blavatnik Family Foundation, the Lymphoma Research Foundation, NHLBI (1RO1HL103532-01; 1RO1HL116452-01) and NCI (1R01CA155010-01A1) and is a recipient of a Leukemia Lymphoma Translational Research Program Award and an AACR SU2C Innovative Research Grant. We thank all members of the Broad Institute’s Biological Samples and Genome Sequencing Platforms, as well as the Cancer Genome Analysis group who made this work possible (NHGRI-U54HG003067).

Author information

Authors and Affiliations

  1. Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA, USA

    D A Landau & C J Wu

  2. Broad Institute, Cambridge, MA, USA

    D A Landau, S L Carter & G Getz

  3. Department of Hematology, Yale Cancer Center, New Haven, CT, USA

    D A Landau

  4. Université Paris Diderot, Paris, France

    D A Landau

  5. Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, MA, USA

    G Getz

  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    C J Wu

  7. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    C J Wu

Authors
  1. D A Landau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S L Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Getz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C J Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C J Wu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Landau, D., Carter, S., Getz, G. et al. Clonal evolution in hematological malignancies and therapeutic implications. Leukemia 28, 34–43 (2014). https://doi.org/10.1038/leu.2013.248

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.248

Keywords

This article is cited by

Search

Advanced search

Quick links