Our understanding of cancer biology has been radically transformed over recent years with a more realistic grasp of its multilayered cellular and genetic complexity. These advances are being translated into more selective and effective treatment of cancers and, although there are still considerable challenges, particularly with drug resistance and metastatic disease, many patients with otherwise lethal malignancies now enjoy protracted remissions or cure. One largely unheralded theme of this story is the extent to which new biological insights and novel clinical applications have their origins with leukaemia and related blood cell cancers, including lymphoma. In this Timeline article, I review the remarkable and ground-breaking role that studies in leukaemia have had at the forefront of this progress.
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Greaves, M. Cancer: The Evolutionary Legacy (Oxford Univ. Press, 2000).
Wright, N. A. Boveri at 100: cancer evolution, from preneoplasia to malignancy. J. Pathol. 234, 146–151 (2014).
Heim, S. & Mitelman, F. Cancer Cytogenetics (Alan R. Liss, 1987).
Nowell, P. & Hungerford, D. A minute chromosome in human granulocytic leukemia. Science 132, 1497 (1960).
Rowley, J. D. Chromosome translocations: dangerous liaisons revisited. Nat. Rev. Cancer 1, 245–250 (2001).
Heisterkamp, N. et al. Localization of the c-abl oncogene adjacent to a translocation breakpoint in chronic myelocytic leukaemia. Nature 306, 239–242 (1983).
Konopka, J. B., Watanabe, S. M. & Witte, O. N. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell 37, 1035–1042 (1984).
Mertens, F., Johansson, B., Fioretos, T. & Mitelman, F. The emerging complexity of gene fusions in cancer. Nat. Rev. Cancer 15, 371–381 (2015).
Dalla-Favera, R. et al. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl Acad. Sci. USA 79, 7824–7827 (1982).
Taub, R. et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl Acad. Sci. USA 79, 7837–7841 (1982).
Cleary, M. L. & Sklar, J. Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc. Natl Acad. Sci. USA 82, 7439–7443 (1985).
Tsujimoto, Y., Gorham, J., Cossman, J., Jaffe, E. & Croce, C. M. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229, 1390–1393 (1985).
Küppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).
Cory, S. & Adams, J. M. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer 2, 647–656 (2002).
Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).
Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007).
Ley, T. J. et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456, 66–72 (2008).
Fialkow, P. J. The origin and development of human tumors studied with cell markers. N. Engl. J. Med. 291, 26–35 (1974).
Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).
Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356–361 (2011).
Welch, J. S. et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264–278 (2012).
Klco, J. M. et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell 25, 379–392 (2014).
Schuh, A. et al. Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns. Blood 120, 4191–4196 (2012).
Egan, J. B. et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 120, 1060–1066 (2012).
Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014).
Yates, L. R. et al. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat. Med. 21, 751–759 (2015).
Sottoriva, A. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc. Natl Acad. Sci. USA 110, 4009–4014 (2013).
Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).
Sottoriva, A. et al. A Big Bang model of human colorectal tumor growth. Nat. Genet. 47, 209–216 (2015).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Boutros, P. C. et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat. Genet. 47, 736–745 (2015).
Potter, N. E. et al. Single-cell mutational profiling and clonal phylogeny in cancer. Genome Res. 23, 2115–2125 (2013).
Navin, N. E. Cancer genomics: one cell at a time. Genome Biol. 15, 452 (2014).
Eirew, P. et al. Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 518, 422–426 (2015).
Yates, L. R. & Campbell, P. J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012).
Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).
Mullighan, C. G. et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377–1380 (2008).
Jiang, Y. et al. Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas. Genome Biol. 15, 432 (2014).
Juric, D. et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature 518, 240–244 (2015).
Marshall, G. M. et al. The prenatal origins of cancer. Nat. Rev. Cancer 14, 277–289 (2014).
Greaves, M. F. & Wiemels, J. Origins of chromosome translocations in childhood leukaemia. Nat. Rev. Cancer 3, 639–649 (2003).
Greaves, M. F., Maia, A. T., Wiemels, J. L. & Ford, A. M. Leukemia in twins: lessons in natural history. Blood 102, 2321–2333 (2003).
Wiemels, J. L. et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 354, 1499–1503 (1999).
Mori, H. et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc. Natl Acad. Sci. USA 99, 8242–8247 (2002).
Strong, S. J. & Corney, G. The Placenta in Twin Pregnancy (Pergamon Press, 1967).
Ma, Y. et al. Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 110, 7429–7433 (2013).
Cazzaniga, G. et al. Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia. Blood 118, 5559–5565 (2011).
Bateman, C. M. et al. Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 115, 3553–3558 (2010).
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).
Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).
Corces-Zimmerman, M. R. & Majeti, R. Pre-leukemic evolution of hematopoietic stem cells: the importance of early mutations in leukemogenesis. Leukemia 28, 2276–2282 (2014).
Zhang, X. et al. Genomic analysis of the clonal origin and evolution of acute promyelocytic leukemia in a unique patient with a very late (17 years) relapse. Leukemia 28, 1751–1754 (2014).
Ford, A. M. et al. Protracted dormancy of pre-leukaemic stem cells. Leukemia 29, 2202–2207 (2015).
Greaves, M. Does everyone develop covert cancer? Nat. Rev. Cancer 14, 209–210 (2014).
Martincorena, I. et al. Tumor evolution: high burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).
Aparicio, S. & Caldas, C. The implications of clonal genome evolution for cancer medicine. N. Engl. J. Med. 368, 842–851 (2013).
Greaves, M. Evolutionary determinants of cancer. Cancer Discov. 5, 806–820 (2015).
Kreso, A. & Dick, J. E. Evolution of the cancer stem cell model. Cell Stem Cell 14, 275–291 (2014).
Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L. & Swanton, C. Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl Med. 4, 127ps10 (2012).
McGranahan, N. & Swanton, C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27, 15–26 (2015).
Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015).
Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).
Pierce, G. B., Shikes, R. & Fink, L. M. Cancer: A Problem of Developmental Biology (Prentice Hall Inc., 1978).
Fialkow, P. J., Denman, A. M., Jacobson, R. J. & Lowenthal, M. N. Chronic myelocytic leukemia: origin of some lymphocytes from leukemic stem cells. J. Clin. Invest. 62, 815–823 (1978).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Sachs, L. Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukaemia. Nature 274, 535–539 (1978).
Beug, H., Hayman, M. J. & Graf, T. Leukaemia as a disease of differentiation: retroviruses causing acute leukaemias in chickens. Cancer Surveys 1, 205–230 (1982).
Greaves, M. F. Differentiation-linked leukaemogenesis in lymphocytes. Science 234, 697–704 (1986).
Küppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nat. Rev. Cancer 5, 251–262 (2005).
Zhu, Y. & Parada, L. F. The molecular and genetic basis of neurological tumours. Nat. Rev. Cancer 2, 616–626 (2002).
Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010).
Alcantara Llaguno, S. R. et al. Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes. Cancer Cell 28, 429–440 (2015).
Greaves, M. in Nathan and Oski's Hematology and Oncology of Infancy and Childhood (eds Orkin, S. H. et al.) 1229–1238 (Elsevier Saunders, 2015).
Paugh, B. S. et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J. Clin. Oncol. 28, 3061–3068 (2010).
Filbin, M. G. & Stiles, C. D. Of brains and blood: developmental origins of glioma diversity? Cancer Cell 28, 403–404 (2015).
Huntly, B. J. & Gilliland, D. G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat. Rev. Cancer 5, 311–321 (2005).
Dick, J. E. Stem cell concepts renew cancer research. Blood 112, 4793–4807 (2008).
Rosen, J. M. & Jordan, C. T. The increasing complexity of the cancer stem cell paradigm. Science 324, 1670–1673 (2009).
Magee, J. A., Piskounova, E. & Morrison, S. J. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21, 283–296 (2012).
Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).
Gentles, A. J., Plevritis, S. K., Majeti, R. & Alizadeh, A. A. Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA 304, 2706–2715 (2010).
Eppert, K. et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 17, 1086–1093 (2011).
Hartwell, K. A. et al. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat. Chem. Biol. 9, 840–848 (2013).
Notta, F. et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362–367 (2011).
Piccirillo, S. G. M. et al. Genetic and functional diversity of propagating cells in glioblastoma. Stem Cell Rep. 4, 7–15 (2015).
Meyer, M. et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc. Natl Acad. Sci. USA 112, 851–856 (2015).
Greaves, M. Cancer stem cells as 'units of selection'. Evol. Appl. 6, 102–108 (2013).
Fong, C. Y. et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 525, 538–542 (2015).
Greaves, M. F. Analysis of the clinical and biological significance of lymphoid phenotypes in acute leukemia. Cancer Res. 41, 4752–4766 (1981).
Chessells, J. M., Hardisty, R. M., Rapson, N. T. & Greaves, M. F. Acute lymphoblastic leukaemia in children: classification and prognosis. Lancet ii, 1307–1309 (1977).
Sallan, S. E. et al. Cell surface antigens: prognostic implications in childhood acute lymphoblastic leukemia. Blood 55, 395–402 (1980).
Greaves, M. F., Janossy, G., Peto, J. & Kay, H. Immunologically defined subclasses of acute lymphoblastic leukaemia in children: their relationship to presentation features and prognosis. Br. J. Haematol. 48, 179–197 (1981).
Swerdlow, S. H. et al. (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC, 2008).
Pui, C.-H., Relling, M. V. & Downing, J. R. Acute lymphoblastic leukemia. N. Engl. J. Med. 350, 1535–1548 (2004).
Armstrong, S. A. & Look, A. T. Molecular genetics of acute lymphoblastic leukemia. J. Clin. Oncol. 23, 6306–6315 (2005).
Hunger, S. P. & Mullighan, C. G. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood 125, 3977–3987 (2015).
Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).
Sadanandam, A. et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 19, 619–625 (2013).
Taylor, M. D. et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123, 465–472 (2012).
Maley, C. C. et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat. Genet. 38, 468–473 (2006).
Mroz, E. A. et al. High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma. Cancer 119, 3034–3042 (2013).
Michor, F. et al. Dynamics of chronic myeloid leukaemia. Nature 435, 1267–1270 (2005).
Pinkel, D. in White Blood: Personal Journeys with Childhood Leukaemia (ed. Greaves, M.) 13–46 (World Scientific, 2008).
Inaba, H., Greaves, M. & Mullighan, C. G. Acute lymphoblastic leukaemia. Lancet 381, 1943–1955 (2013).
Bhojwani, D. et al. ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia 26, 265–270 (2012).
Newlands, E. S. et al. Developments in chemotherapy for medium- and high-risk patients with gestational trophoblastic tumours (1979–1984). Br. J. Obstet. Gynaecol. 93, 63–69 (1986).
Horwich, A., Nicol, D. & Huddart, R. Testicular germ cell tumours. BMJ 347, f5526 (2013).
Papaemmanuil, E. et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6–RUNX1 acute lymphoblastic leukemia. Nat. Genet. 46, 116–125 (2014).
Litchfield, K. et al. Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat. Commun. 6, 5973 (2015).
Gutekunst, M. et al. p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS ONE 6, e19198 (2011).
Al-Lazikani, B., Banerji, U. & Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30, 679–692 (2012).
Druker, B. J. Perspectives on the development of imatinib and the future of cancer research. Nat. Med. 15, 1149–1152 (2009).
Corbin, A. S. et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J. Clin. Invest. 121, 396–409 (2011).
Sosa, M. S., Bragado, P. & Aguirre-Ghiso, J. A. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).
Zhang, B. et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 17, 427–442 (2010).
Essers, M. A. & Trumpp, A. Targeting leukemic stem cells by breaking their dormancy. Mol. Oncol. 4, 443–450 (2010).
Roche-Lestienne, C. 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 100, 1014–1018 (2002).
Pfeifer, H. et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 110, 727–734 (2007).
Shih, A. H., Abdel-Wahab, O., Patel, J. P. & Levine, R. L. The role of mutations in epigenetic regulators in myeloid malignancies. Nat. Rev. Cancer 12, 599–612 (2012).
Lotem, J. & Sachs, L. Epigenetics wins over genetics: induction of differentiation in tumor cells. Semin. Cancer Biol. 12, 339–346 (2002).
Wang, Z. Y. & Chen, Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111, 2505–2515 (2008).
Zhu, J., Chen, Z., Lallemand-Breitenbach, V. & de The, H. How acute promyelocytic leukaemia revived arsenic. Nat. Rev. Cancer 2, 705–713 (2002).
Ablain, J. et al. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nat. Med. 20, 167–174 (2014).
Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012).
Zhang, X., Cruz, F. D., Terry, M., Remotti, F. & Matushansky, I. Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Oncogene 32, 2249–2260 (2013).
Cruz, F. D. & Matushansky, I. Solid tumor differentiation therapy – is it possible? Oncotarget 3, 559–567 (2012).
Laugesen, A. & Helin, K. Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell 14, 735–751 (2014).
Sykes, S. M. et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146, 697–708 (2011).
Thomas, E. D. Bone marrow transplantation: a review. Semin. Hematol. 36, 95–103 (1999).
Nivison-Smith, I. et al. Relative survival of long-term hematopoietic cell transplant recipients approaches general population rates. Biol. Blood Marrow Transplant. 15, 1323–1330 (2009).
Jenq, R. R. & van den Brink, M. R. Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat. Rev. Cancer 10, 213–221 (2010).
Klein, C. A. Parallel progression of primary tumours and metastases. Nat. Rev. Cancer 9, 302–312 (2009).
Pietras, W. Advances and changes in the treatment of children with nephroblastoma. Adv. Clin. Exp. Med. 21, 809–820 (2012).
Necchi, A. et al. High-dose chemotherapy for germ cell tumors: do we have a model? Expert Opin. Biol. Ther. 15, 33–44 (2015).
Sureda, A. et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 50, 1037–1056 (2015).
Demirer, T. et al. Transplantation of allogeneic hematopoietic stem cells: an emerging treatment modality for solid tumors. Nat. Clin. Pract. Oncol. 5, 256–267 (2008).
Bachireddy, P., Burkhardt, U. E., Rajasagi, M. & Wu, C. J. Haematological malignancies: at the forefront of immunotherapeutic innovation. Nat. Rev. Cancer 15, 201–215 (2015).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Larson, S. M., Carrasquillo, J. A., Cheung, N. K. & Press, O. W. Radioimmunotherapy of human tumours. Nat. Rev. Cancer 15, 347–360 (2015).
Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Weiner, G. J. Building better monoclonal antibody-based therapeutics. Nat. Rev. Cancer 15, 361–370 (2015).
Adams, G. P. & Weiner, L. M. Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23, 1147–1157 (2005).
Miller, J. F. & Sadelain, M. The journey from discoveries in fundamental immunology to cancer immunotherapy. Cancer Cell 27, 439–449 (2015).
Reiss, K. A., Forde, P. M. & Brahmer, J. R. Harnessing the power of the immune system via blockade of PD-1 and PD-L1: a promising new anticancer strategy. Immunotherapy 6, 459–475 (2014).
Rizvi, N. A. et al. Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Szczepanski, T., Orfao, A., van der Velden, V. H., San Miguel, J. F. & van Dongen, J. J. Minimal residual disease in leukaemia patients. Lancet Oncol. 2, 409–417 (2001).
van Dongen, J. J. M. et al. Prognostic value of minimal residual disease in childhood acute lymphoblastic leukemia. Lancet 352, 1731–1738 (1998).
van Dongen, J. J., van der Velden, V. H., Bruggemann, M. & Orfao, A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood 125, 3996–4009 (2015).
Hourigan, C. S. & Karp, J. E. Minimal residual disease in acute myeloid leukaemia. Nat. Rev. Clin. Oncol. 10, 460–471 (2013).
Bettegowda, C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl Med. 6, 224ra24 (2014).
Dawson, S. J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).
Garcia-Murillas, I. et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci. Transl Med. 7, 302ra133 (2015).
Franceschi, S. & Herrero, R. in IARC World Cancer Report 2014 (eds Stewart, B. W. & Wild, C. P.) 105–114 (IARC, 2014).
Zur Hausen, H. Infections Causing Human Cancer (Wiley-VCH, 2006).
Cohen, J. I., Fauci, A. S., Varmus, H. & Nabel, G. J. Epstein-Barr virus: an important vaccine target for cancer prevention. Sci. Transl Med. 3, 107fs7 (2011).
Moore, P. S. & Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer 10, 878–889 (2010).
Ellermann, V. & Bang, O. Experimentelle Leukämie bei Hühnern. Zentralbl. Bakteriol. 46, 595 (1908).
Rous, P. A sarcoma of the fowl transmissible by agent separable from tumor cells. J. Exp. Med. 13, 397–411 (1911).
Gross, L. Oncogenic Viruses (Pergamon Press, 1983).
Jarrett, W. F., Crawford, E. M., Martin, W. B. & Davie, F. A. Virus-like particle associated with leukemia (lymphosarcoma). Nature 202, 567–569 (1964).
Hardy, W. D. et al. Horizontal transmission of feline leukaemia virus. Nature 244, 266–269 (1973).
Burny, A. et al. Bovine leukemia virus involvement in enzootic bovine leukosis. Adv. Cancer Res. 28, 251–311 (1978).
Jarrett, W. et al. Vaccination against feline leukaemia virus using a cell membrane antigen system. Int. J. Cancer 16, 134–141 (1975).
Epstein, M. A., Achong, B. G. & Barr, Y. M. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet i, 702–703 (1964).
Gallo, R. C., Essex, M. E. & Gross, L. (eds) Human T-cell Leukemia/Lymphoma Virus: The Family of Human T-Lymphotropic Retroviruses: Their Role in Malignancies and Association with AIDS (Cold Spring Harbor Laboratory Press, 1984).
Matsuoka, M. & Jeang, K. T. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat. Rev. Cancer 7, 270–280 (2007).
Isaacson, P. G. & Du, M.-Q. MALT lymphoma: from morphology to molecules. Nat. Rev. Cancer 4, 644–653 (2004).
Peek, R. M. Jr & Blaser, M. J. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat. Rev. Cancer 2, 28–37 (2002).
Schulz, M. D. et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514, 508–512 (2014).
Arthur, J. C. et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012).
Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).
Cuzick, J. et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 10, 501–507 (2009).
Kostadinov, R. L. et al. NSAIDs modulate clonal evolution in Barrett's esophagus. PLoS Genet. 9, e1003553 (2013).
Stewart, B. W. & Wild, C. P. (eds) World Cancer Report 2014 (IARC, 2014).
Medawar, P. B. The Art of the Soluble (Methuen & Co. Ltd, 1967).
Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).
Wang, J. C. Y. & Dick, J. E. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 15, 494–501 (2005).
Metcalf, D. Hematopoietic cytokines. Blood 111, 485–491 (2008).
Wyke, J. & Weiss, R. (eds) Cancer Surveys: Viruses in Human and Animal Cancers (Oxford Univ. Press, 1984).
Herzenberg, L. A. et al. The history and future of the fluorescence activated cell sorter and flow cytometry: a view from Stanford. Clin. Chem. 48, 1819–1827 (2002).
Piller, G. Rays of Hope – The Story of the Leukaemia Research Fund (Leukaemia Research Fund, 1994).
Luch, A. Nature and nurture – lessons from chemical carcinogenesis. Nat. Rev. Cancer 5, 113–125 (2005).
Tabin, C. J. et al. Mechanism of activation of a human oncogene. Nature 300, 143–149 (1982).
Reddy, E. P., Reynolds, R. K., Santos, E. & Barbacid, M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300, 149–152 (1982).
Zetter, B. R. The scientific contributions of M. Judah Folkman to cancer research. Nat. Rev. Cancer 8, 647–654 (2008).
Campbell, P. J. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat. Genet. 40, 722–729 (2008).
Fletcher, O. & Houlston, R. S. Architecture of inherited susceptibility to common cancer. Nat. Rev. Cancer 10, 353–361 (2010).
Lenoir, G. M., O'Conor, G. T. & Olweny, C. L. M. (eds) Burkitt's Lymphoma: A Human Cancer Model (WHO/IARC, 1985).
Burkitt, D. P. in Burkitt's Lymphoma: A Human Cancer Model (eds Lenoir, G. M., O'Conor, G. T. & Olwany, C. L. M.) 11–15 (IARC, 1985).
Boshoff, C. & Weiss, R. AIDS-related malignancies. Nat. Rev. Cancer 2, 373–382 (2002).
Young, L. S. & Rickinson, A. B. Epstein-Barr virus: 40 years on. Nat. Rev. Cancer 4, 757–768 (2004).
Laszlo, J. The Cure of Childhood Leukaemia (Rutgers Univ. Press, 1995).
M.G. is supported by Leukaemia & Lymphoma Research (now Bloodwise), the Wellcome Trust [105104/Z/14/Z] and The Institute of Cancer Research. The author is very grateful to Professor T. Andrew Lister, a friend and colleague who helped to introduce him to clinical leukaemia many years ago and has provided constructive suggestions on this article. This historical Timeline article covers a time frame of many decades and an extensive field of biomedical research and clinical endeavour. The author apologizes for the inevitable omissions; it's a complex narrative.
The author declares no competing financial interests.
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Greaves, M. Leukaemia 'firsts' in cancer research and treatment. Nat Rev Cancer 16, 163–172 (2016). https://doi.org/10.1038/nrc.2016.3
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