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 Article
  • Published:

Origins of chromosome translocations in childhood leukaemia

Key Points

  • Different subtypes of leukaemia have distinctive chromosome translocations.

  • Translocations seem to arise at the level of haematopoietic stem cells, but their impact is cell-context dependent, resulting in different effects in different lineages.

  • Chromosome translocations are initiated by double-strand DNA breaks. The main repair mechanism underlying the resultant illegitimate recombination is probably non-homologous end-joining.

  • The products of balanced chromosome translocations are fusion genes, generating either a dysregulated partner gene or a chimeric fusion protein with new properties (either altered transcriptional regulation or constitutive kinase activity).

  • In childhood leukaemia, chromosome translocations arise mainly before birth during fetal haematopoiesis.

  • Chromosome translocations can initiate leukaemogenesis, but are usually not sufficient, with additional postnatal events being required.

  • The detailed understanding of chromosome translocations has implications for differential diagnosis, new therapies and molecular epidemiological studies that aim to uncover causality.

Abstract

Chromosome translocations are often early or initiating events in leukaemogenesis, occurring prenatally in most cases of childhood leukaemia. Although these genetic changes are necessary, they are usually not sufficient to cause leukaemia. How, when and where do translocations arise? And can these insights aid our understanding of the natural history, pathogenesis and causes of leukaemia?

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Breakpoint cluster regions (BCRs) in TEL and AML1, the common fusion genes of childhood leukaemia.
Figure 2: Causes and consequences of DNA breaks leading to translocations.
Figure 3: Presumptive stem-cell origins of chromosome translocations in childhood leukaemia.
Figure 4: Concordant acute leukaemia in identical twins share identical (clonotypic) genomic rearrangements.

Similar content being viewed by others

References

  1. Kersey, J. H. Fifty years of studies of the biology and therapy of childhood leukemia. Blood 90, 4243–4251 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Biondi, A., Cimino, G., Pieters, R. & Pui, C. -H. Biological and therapeutic aspects of infant leukemia. Blood 96, 24–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Raimondi, S. C. in Childhood Leukemias. (ed. Pui, C.-H.) 168–196 (Cambridge Univ. Press, Cambridge, 1999).

    Google Scholar 

  4. Look, A. T. Oncogenic transcription factors in the human acute leukemias. Science 278, 1059–1064 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Yeoh, E. -J. et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1, 133–143 (2002). A key paper highlighting the potential of gene-expression profiling to provide new insights into the biological classification and prognosis of leukaemia.

    Article  CAS  PubMed  Google Scholar 

  6. Armstrong, S. A. et al. MLL translocations specify a distinct gene expression profile, distinguishing a unique leukemia. Nature Genet. 30, 41–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Schoch, C. et al. Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc. Natl Acad. Sci. USA 99, 10008–10013 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rabbitts, T. H. Chromosomal translocations in human cancer. Nature 372, 143–149 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Rowley, J. D. The critical role of chromosome translocations in human leukemias. Annu. Rev. Genet. 32, 495–519 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Lengauer, C. How do tumors make ends meet? Proc. Natl Acad. Sci. USA 98, 12331–12333 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Romana, S. P. et al. The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion. Blood 85, 3662–3670 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Golub, T. R. et al. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 92, 4917–4921 (1995). References 11 and 12 describe the co-discovery of the most common fusion gene in childhood leukaemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shurtleff, S. A. et al. TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9, 1985–1989 (1995).

    CAS  PubMed  Google Scholar 

  14. Enver, T. & Greaves, M. Loops, lineage, and leukemia. Cell 94, 9–12 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Tenen, D. G. Disruption of differentiation in human cancer: AML shows the way. Nature Rev. Cancer 3, 89–101 (2003).

    Article  CAS  Google Scholar 

  16. Speck, N. A. & Gilliland, D. G. Core-binding factors in haematopoiesis and leukaemia. Nature Rev. Cancer 2, 502–513 (2002).

    Article  CAS  Google Scholar 

  17. Wiemels, J. L. et al. Site-specific translocation and evidence of post-natal origin of the t(1;19) E2A-PBX1 translocation in childhood acute lymphoblastic leukemia. Proc. Natl Acad. Sci., USA 99, 15101–15106 (2003).

    Article  CAS  Google Scholar 

  18. Reichel, M. et al. Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation. Oncogene 17, 3035–3044 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Wiemels, J. L. & Greaves, M. Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer Res. 59, 4075–4082 (1999).

    CAS  PubMed  Google Scholar 

  20. Xiao, Z. et al. Molecular characterization of genomic AML1-ETO fusions in childhood leukemia. Leukemia 15, 1906–1913 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Wiemels, J. L. et al. Microclustering of TEL-AML1 translocation breakpoints in childhood acute lymphoblastic leukemia. Genes Chromosom. Cancer 29, 219–228 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Reiter, A. et al. Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia. Genes Chromosom. Cancer 36, 175–188 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Khanna, K. K. & Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nature Genet. 27, 247–254 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Chu, G. Double strand break repair. J. Biol. Chem. 272, 24097–24100 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Kanaar, R., Hoeijmakers, J. H. J. & van Gent, D. C. Molecular mechanisms of DNA double-strand break repair. Trends Cell. Biol. 8, 483–489 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Haluska, F. G., Finger, L. R., Kagan, J. & Croce, C. M. in Molecular Genetics in Cancer Diagnosis (ed. Cossman, J.) 143–162 (Elsevier, New York, 1990).

    Google Scholar 

  27. Küppers, R. & Dalla–Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).

    Article  PubMed  Google Scholar 

  28. Brown, L. et al. Site-specific recombination of the tal-1 gene is a common occurrence in human T cell leukemia. EMBO J. 9, 3343–3351 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. van der Reijden, B. A. et al. Genomic acute myeloid leukemia-associated inv(16)(p13q22) breakpoints are tightly clustered. Oncogene 18, 543–550 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Kitagawa, Y. et al. Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia. J. Biol. Chem. 12, 12 (2002).

    Google Scholar 

  31. Lewis, S. M., Agard, E., Suh, S. & Czyzyk, L. Cryptic signals and the fidelity of V(D)J joining. Mol. Cell. Biol. 17, 3125–3136 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Raghavan, S. C., Kirsch, I. R. & Lieber, M. R. Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints. J. Biol. Chem. 276, 29126–29133 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Marculescu, R., Le, T., Simon, P., Jaeger, U. & Nadel, B. V(D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. J. Exp. Med. 195, 85–98 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Agrawal, A., Eastman, Q. M. & Schatz, D. G. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394, 744–751 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Hiom, K., Melck, M. & Gellert, M. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94, 463–470 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Liu, Y., Hernandez, A. M., Shibata, D. & Cortopassi, G. A. BCL2 translocation frequency rises with age in humans. Proc. Natl Acad. Sci. USA 91, 8910–8914 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Marculescu, R. et al. Distinct t(7;9)(q34;q32) breakpoints in healthy individuals and individuals with T-ALL. Nature Genet. 33, 342–344 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, J. C. DNA topoisomerases. Annu. Rev. Biochem. 65, 635–692 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Pedersen–Bjergaard, J. & Rowley, J. D. The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation. Blood 83, 2780–2786 (1994).

    Article  PubMed  Google Scholar 

  40. Felix, C. A. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim. Biophys. Acta 1400, 233–255 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Rowley, J. D. & Olney, H. J. International workshop on the relationship of prior therapy to balanced chromosome aberrations in therapy-related myelodysplastic syndromes and acute leukemia: overview report. Genes Chromosom. Cancer 33, 331–345 (2002).

    Article  PubMed  Google Scholar 

  42. Han, Y. H., Austin, M. J., Pommier, Y. & Povirk, L. F. Small deletion and insertion mutations induced by the topoisomerase II inhibitor teniposide in CHO cells and comparison with sites of drug-stimulated DNA cleavage in vitro. J. Mol. Biol. 229, 52–66 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Felix, C. A., Lange, B. J., Hosler, M. R., Fertala, J. & Bjornsti, M. A. Chromosome band 11q23 translocation breakpoints are DNA topoisomerase II cleavage sites. Cancer Res. 55, 4287–4292 (1995).

    CAS  PubMed  Google Scholar 

  44. Lovett, B. D. et al. Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. Proc. Natl Acad. Sci. USA 98, 9802–9807 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhou, R. H., Wang, P., Zou, Y., Jackson–Cook, C. K. & Povirk, L. F. A precise interchromosomal reciprocal exchange between hot spots for cleavable complex formation by topoisomerase II in amsacrine-treated Chinese hamster ovary cells. Cancer Res. 57, 4699–4702 (1997).

    CAS  PubMed  Google Scholar 

  46. Ahuja, H. G., Felix, C. A. & Aplan, P. D. Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Genes Chromosom. Cancer 29, 96–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Blanco, J. G. et al. Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 98, 10338–10343 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Betti, C. J., Villalobos, M. J., Diaz, M. O. & Vaughan, A. T. M. Apoptotic stimuli initiate MLL-AF9 translocations that are transcribed in cells capable of division. Cancer Res. 63, 1377–1381 (2003).

    CAS  PubMed  Google Scholar 

  49. Aplan, P. D., Chervinsky, D. S., Stanulla, M. & Burhans, W. C. Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors. Blood 87, 2649–2658 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Broeker, P. L. S. et al. Distribution of 11q23 breakpoints within the MLL breakpoint cluster region in de novo acute leukemia and in treatment-related acute myeloid leukemia: Correlation with scaffold attachment regions and topoisomerase II consensus binding sites. Blood 87, 1912–1922 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Strick, R., Strissel, P. L., Borgers, S., Smith, S. L. & Rowley, J. D. Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc. Natl Acad. Sci. USA 97, 4790–4795 (2000). The first experimental demonstration that bioflavonoid substances can induce breaks in the MLL gene. This information underpins current epidemiological studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Strissel, P. L., Strick, R., Rowley, J. D. & Zeleznik–Le, N. J. An in vivo topoisomerase II cleavage site and a DNase I hypersensitive site colocalize near exon 9 in the MLL breakpoint cluster region. Blood 92, 3793–3803 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Betti, C. J., Villalobos, M. J., Diaz, M. O. & Vaughan, A. T. Apoptotic triggers initiate translocations within the MLL gene involving the nonhomologous end joining repair system. Cancer Res. 61, 4550–4555 (2001).

    CAS  PubMed  Google Scholar 

  54. Stanulla, M., Wang, J., Chervinsky, D. S., Thandla, S. & Aplan, P. D. DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. Mol. Cell. Biol. 17, 4070–4079 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sim, S. P. & Liu, L. F. Nucleolytic cleavage of the mixed lineage leukemia breakpoint cluster region during apoptosis. J. Biol. Chem. 276, 31590–31595 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Alam, A., Cohen, L. Y., Aouad, S. & Sekaly, R. P. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J. Exp. Med. 190, 1879–1890 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Eguchi–Ishimae, M. et al. Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals. Blood 97, 737–743 (2001).

    Article  PubMed  Google Scholar 

  59. Stanulla, M., Wang, J., Chervinsky, D. S. & Aplan, P. D. Topoisomerase II inhibitors induce DNA double-strand breaks at a specific site within the AML1 locus. Leukemia 11, 490–496 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Strissel, P. L. et al. DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis. Hum. Mol. Genet. 9, 1671–1679 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Zhang, Y. et al. Genomic DNA breakpoints in AML1/RUNX1 and ETO cluster with topoisomerase II DNA cleavage and DNase I hypersensitive sites in t(8;21) leukemia. Proc. Natl Acad. Sci. USA 99, 3070–3075 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Richardson, C. & Jasin, M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697–700 (2000). An elegant demonstration that chromosome translocations can be experimentally induced by DNA breaks.

    Article  CAS  PubMed  Google Scholar 

  63. Kolomietz, E., Meyn, M. S., Pandita, A. & Squire, J. A. The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors. Genes Chromosom. Cancer 35, 97–112 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Rudiger, N. S., Gregersen, N. & Kielland–Brandt, M. C. One short well conserved region of Alu-sequences is involved in human gene rearrangements and has homology with prokaryotic chi. Nucl. Acids Res. 23, 256–260 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jeffs, A. R., Benjes, S. M., Smith, T. L., Sowerby, S. J. & Morris, C. M. The BCR gene recombines preferentially with Alu elements in complex BCR-ABL translocations of chronic myeloid leukaemia. Hum. Mol. Genet. 7, 767–776 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Saglio, G. et al. A 76-kb duplicon maps close to the BCR gene on chromosome 22 and the ABL gene on chromosome 9: possible involvement in the genesis of the Philadelphia chromosome translocation. Proc. Natl Acad. Sci. USA 99, 9882–9887 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. So, C. W. et al. MLL self fusion mediated by Alu repeat homologous recombination and prognosis of AML-M4/M5 subtypes. Cancer Res. 57, 117–122 (1997).

    CAS  PubMed  Google Scholar 

  68. Strout, M. P., Marcucci, G., Bloomfield, C. D. & Caligiuri, M. A. The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia. Proc. Natl Acad. Sci. USA 95, 2390–2395 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sekiguchi, J. M. et al. Nonhomologous end-joining proteins are required for V(D)J recombination, normal growth, and neurogenesis. Cold Spring Harb. Symp. Quant. Biol. 64, 169–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Ferguson, D. O. et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc. Natl Acad. Sci., USA 97, 6630–6633 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rothkamm, K., Kuhne, M., Jeggo, P. A. & Lobrich, M. Radiation-induced genomic rearrangements formed by nonhomologous end-joining of DNA double-strand breaks. Cancer Res. 61, 3886–3893 (2001).

    CAS  PubMed  Google Scholar 

  72. Rowley, J. D. Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Res. 44, 3159–3168 (1984).

    CAS  PubMed  Google Scholar 

  73. McCulloch, E. Stem cells in normal and leukemic hemopoiesis. Blood 62, 1–13 (1983).

    Article  CAS  PubMed  Google Scholar 

  74. Greaves, M. Cancer. The Evolutionary Legacy (Oxford Univ. Press, Oxford, 2000).

    Google Scholar 

  75. Pierce, G. B., Shikes, R. & Fink, L. M. Cancer: A Problem of Developmental Biology (Prentice Hall Inc, New Jersey, 1978).

    Google Scholar 

  76. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Weissman, I. L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157–168 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Fuchs, E. & Segre, J. A. Stem cells: a new lease on life. Cell 100, 143–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Fialkow, P. J. in Genes and Cancer (eds. Bishop, J. M., Rowley, J. D. & Greaves, M. F.) 215–226 (Alan R Liss, New York, 1984).

    Google Scholar 

  80. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997). A key paper that identifies multipotential stem cells as the common target for genetic abnormalities in myeloid leukaemia.

    Article  CAS  PubMed  Google Scholar 

  81. Barr, F. G. Translocations, cancer and the puzzle of specificity. Nature Genet. 19, 121–124 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Griffiths, S. D. et al. Clonal characteristics of acute lymphoblastic cells derived from BCR/ABL p190 transgenic mice. Oncogene 7, 1391–1399 (1992).

    CAS  PubMed  Google Scholar 

  83. Corral, J. et al. An Mll–AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell 85, 853–861 (1996).

    Article  CAS  PubMed  Google Scholar 

  84. Greaves, M. F. Stem cell origins of leukaemia and curability. Br. J. Cancer 67, 413–423 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Greaves, M., Maia, A. T., Wiemels, J. L. & Ford, A. M. Leukemia in twins: lessons in natural history. Blood (in the press).

  86. Senator, H. Zur Kenntniss der Leukämie und Pseudoleukämie im Kindesalter. Berliner Klinische Wochenschrift 35, 533–536 (1882).

    Google Scholar 

  87. Clarkson, B. & Boyse, E. A. Possible explanation of the high concordance for acute leukaemia in monozygotic twins. Lancet 1, 699–701 (1971).

    Article  CAS  PubMed  Google Scholar 

  88. Ford, A. M. et al. In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Nature 363, 358–360 (1993). The first demonstration that chromosome translocations can arise prenatally.

    Article  CAS  PubMed  Google Scholar 

  89. Gill Super, H. J. et al. Clonal, nonconsitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23. Blood 83, 641–644 (1994).

    Article  CAS  PubMed  Google Scholar 

  90. Megonigal, M. D. et al. t(11;22)(q23;q11. 2) in acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes. Proc. Natl Acad. Sci. USA 95, 6413–6418 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ford, A. M. et al. Fetal origins of the TEL–AML1 fusion gene in identical twins with leukemia. Proc. Natl Acad. Sci. USA 95, 4584–4588 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wiemels, J. L., Ford, A. M., Van Wering, E. R., Postma, A. & Greaves, M. Protracted and variable latency of acute lymphoblastic leukemia after TEL–AML1 gene fusion in utero. Blood 94, 1057–1062 (1999). A paper showing that leukaemias initiated prenatally can have protracted postnatal latencies (of 14 years).

    Article  CAS  PubMed  Google Scholar 

  93. Maia, A. T. et al. Molecular tracking of leukemogenesis in a triplet pregnancy. Blood 98, 478–482 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Ford, A. M. et al. Monoclonal origin of concordant T-cell malignancy in identical twins. Blood 89, 281–285 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Maia, A. T. et al. Pre-natal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia (in the press).

  96. Greaves, M. Molecular genetics, natural history and the demise of childhood leukaemia. Eur. J. Cancer 35, 173–185 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Gale, K. B. et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc. Natl Acad. Sci. USA 94, 13950–13954 (1997). A key paper providing the first evidence that leukaemia fusion genes are present and detectable in the archived neonatal blood spots of patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wiemels, J. L. et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 354, 1499–1503 (1999). Definitive study of the prenatal origins of childhood acute lymphoblastic leukaemia.

    Article  CAS  PubMed  Google Scholar 

  99. Wiemels, J. L. et al. In utero origin of t(8;21) AML1–ETO translocations in childhood acute myeloid leukemia. Blood 99, 3801–3805 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Yagi, T. et al. Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia. Blood 96, 264–268 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Fasching, K. et al. Presence of clone-specific antigen receptor gene rearrangements at birth indicates an in utero origin of diverse types of early childhood acute lymphoblastic leukemia. Blood 95, 2722–2724 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Taub, J. W. et al. High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 99, 2992–2996 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Panzer–Grümayer, E. R. et al. Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis. Blood 100, 347–349 (2002).

    Article  PubMed  CAS  Google Scholar 

  104. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Yuan, Y. et al. AML1–ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc. Natl Acad. Sci. USA 98, 10398–10403 (2001). An elegant paper showing that common chromosome translocations in leukaemia have to be complemented by other genetic abnormalities to produce overt leukaemias.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Higuchi, M. et al. Expression of a conditional AML1–ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1, 63–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990). Shows that human leukaemia can be mimicked in mice using the appropriate leukaemia gene ( BCR–ABL ) as a transgene.

    Article  CAS  PubMed  Google Scholar 

  108. Era, T. & Witte, O. N. Regulated expression of P210 Bcr–Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate. Proc. Natl Acad. Sci. USA 97, 1737–1742 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Deininger, M. W. N., Goldman, J. M. & Melo, J. V. The molecular biology of chronic myeloid leukaemia. Blood 96, 3343–3356 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Andreasson, P., Schwaller, J., Anastasiadou, E., Aster, J. & Gilliland, D. G. The expression of ETV6/CBF2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo. Cancer Genet. Cytogenet. 130, 93–104 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Bernardin, F. et al. TEL–AML1, expressed from t(12;21) in human acute lymphocytic leukemia, induces acute leukemia in mice. Cancer Res. 62, 3904–3908 (2002).

    CAS  PubMed  Google Scholar 

  112. Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. J. & Korsmeyer, S. J. Altered hox expression and segmental identity in Mll-mutant mice. Nature 378, 505–508 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Raynaud, S. et al. The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood 87, 2891–2899 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Romana, S. P. et al. Deletion of the short arm of chromosome 12 is a secondary event in acute lymphoblastic leukemia with t(12;21). Leukemia 10, 167–170 (1996).

    CAS  PubMed  Google Scholar 

  116. Ford, A. M. et al. Origins of 'late' relapse in childhood acute lymphoblastic leukemia with TEL-AML1 fusion genes. Blood 98, 558–564 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Van Rompaey, L., Potter, M., Adams, C. & Grosveld, G. Tel induces a G1 arrest and suppresses Ras-induced transformation. Oncogene 19, 5244–5250 (2000).

    Article  CAS  Google Scholar 

  118. Lopez, R. G. et al. TEL is a sequence-specific transcriptional repressor. J. Biol. Chem. 274, 30132–30138 (1999).

    Article  CAS  PubMed  Google Scholar 

  119. McLean, T. W. et al. TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 88, 4252–4258 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Armstrong, S. A. et al. Inhibition of FLT3 in MLL: validation of a therapeutic target identified by gene expression based classification. Cancer Cell 3, 173–183 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Gilliland, D. G. & Griffin, J. D. The roles of FLT3 in hematopoiesis and leukemia. Blood 100, 1532–1542 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Knudson, A. G. Stem cell regulation, tissue ontogeny, and oncogenic events. Semin. Cancer Biol. 3, 99–106 (1992).

    CAS  PubMed  Google Scholar 

  123. Biernaux, C., Loos, M., Sels, A., Huez, G. & Stryckmans, P. Detection of major bcr–abl gene expression at a very low level in blood cells of some healthy individuals. Blood 86, 3118–3122 (1995).

    Article  CAS  PubMed  Google Scholar 

  124. Bose, S., Deininger, M., Gora–Tybor, J., Goldman, J. M. & Melo, J. V. The presence of typical and atypical BCR–ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 92, 3362–3367 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. 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). First paper identifying cells carrying common chromosome translocations in blood from normal newborns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Miyamoto, T., Weissman, I. L. & Akashi, K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc. Natl Acad. Sci. USA 97, 7521–7526 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Szczepanski, T. & van Dongen, J. J. M. in Leukemia (eds. Henderson, E. S., TA, L. & Greaves, M. F.) 249–283 (Saunders, Philadelphia, 2002).

    Google Scholar 

  128. Fenaux, P., Chomienne, C. & Degos, L. Treatment of acute promyelocytic leukaemia. Best Pract. Res. Clin. Haematol. 14, 153–174 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Druker, B. 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. 344, 1038–1042 (2001). An important paper setting the precedent for successful therapy derived from targeting the molecular lesion in leukaemia.

    Article  CAS  PubMed  Google Scholar 

  130. Redner, R. L., Wang, J. & Liu, J. Chromatin remodeling and leukemia: new therapeutic paradigms. Blood 94, 417–428 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Rabbitts, T. H. & Stocks, M. R. Chromosomal translocation products engender new intracellular therapeutic technologies. Nature Med. 9, 383–386 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Roix, J. J., McQueen, P. G., Munson, P. J., Parada, L. A. & Misteli, T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nature Genet. 34, 287–291 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Greaves, M. F. Aetiology of acute leukaemia. Lancet 349, 344–349 (1997).

    Article  CAS  PubMed  Google Scholar 

  134. Ross, J. A., Potter, J. D. & Robison, L. L. Infant leukemia, topoisomerase II inhibitors, and the MLL gene. J. Natl Cancer Inst. 86, 1678–1680 (1994).

    Article  CAS  PubMed  Google Scholar 

  135. Wiemels, J. L. et al. A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. Cancer Res. 59, 4095–4099 (1999).

    CAS  PubMed  Google Scholar 

  136. Alexander, F. E. et al. Transplacental chemical exposure and risk of infant leukaemia with MLL gene fusion. Cancer Res. 61, 2542–2546 (2001).

    CAS  PubMed  Google Scholar 

  137. Ma, X. et al. Daycare attendance and risk of childhood acute lymphoblastic leukaemia. Br. J. Cancer 86, 1419–1424 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Perrillat, F. et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br. J. Cancer 86, 1064–1069 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wiemels, J. L. et al. Methylene tetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc. Natl Acad. Sci. USA 98, 4004–4009 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Thompson, J. R., Fitz Gerald, P., Willoughby, M. L. N. & Armstrong, B. K. Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. Lancet 358, 1935–1940 (2001).

    Article  CAS  PubMed  Google Scholar 

  141. Hjalgrim, L. L. et al. Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia. Br. J. Cancer 87, 994–999 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. McHale, C. M. et al. Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16). Blood 101, 4640–4641 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Schneider, T. D., Stormo, G. D., Gold, L. & Ehrenfeucht, A. Information content of binding sites on nucleotide sequences. J. Mol. Biology 188, 415–431 (1986).

    Article  CAS  Google Scholar 

  144. Fialkow, P. J. et al. Clonal development, stem-cell differentiation, and clinical remissions in acute nonlymphocytic leukemia. N. Engl J. Med. 317, 468–473 (1987).

    Article  CAS  PubMed  Google Scholar 

  145. Hotfilder, M. et al. Immature CD34+CD19 progenitor/stem cells in TEL/AML1-positive acute lymphoblastic leukemia are genetically and functionally normal. Blood 100, 640–646 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Greaves, M. F. Differentiation-linked leukaemogenesis in lymphocytes. Science 234, 697–704 (1986).

    Article  CAS  PubMed  Google Scholar 

  147. Ridge, S. A. et al. Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement. Leukemia 9, 2023–2026 (1995).

    CAS  PubMed  Google Scholar 

  148. Cumano, A., Paige, C. J., Iscove, N. N. & Brady, G. Bipotential precursors of B cells and macrophages in murine fetal liver. Nature 356, 612–615 (1992).

    Article  CAS  PubMed  Google Scholar 

  149. Kalousek, D. K., Dube, I. D., Eaves, C. J. & Eaves, A. C. Cytogenetic studies of haemopoietic colonies from patients with an initial diagnosis of acute lymphoblastic leukaemia. Br. J. Haematol. 70, 5–11 (1988).

    Article  CAS  PubMed  Google Scholar 

  150. Cobaleda, C. et al. A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood 95, 1007–1013 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Kempski, H. et al. Prenatal chromosomal diversification of leukemia in monozygotic twins. Genes Chromosom. Cancer 37, 406–411 (2003).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

M.G. is supported by a specialist programme grant from the Leukaemia Research Fund, UK.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mel F. Greaves.

Related links

Related links

DATABASES

Cancer.gov

leukaemia

LocusLink

AF4

AML1

BCR

E2A

ETO

LMO2

MLL

MYC

NUP98

PBX1

PML

RARA

TEL

TOP1

FURTHER INFORMATION

Mitelman Database of Chromosome Aberrations in Cancer

Glossary

HYPERDIPLOIDY

A common genetic abnormality in childhood leukaemia that is characterized by an extra copy (that is, triploidy) of particular chromosomes.

V(D)J RECOMBINATION

The somatic rearrangement of variable (V), diversity (D) and joining (J) regions of antigen-receptor-encoding genes, which leads to the repertoire diversity of both T- and B-cell receptors.

RECOMBINATION SIGNAL SEQUENCES

(RSSs). Short stretches of conserved heptamer and nonamer sequences (separated by a spacer sequence) in V and D segments that are required for the recognition and recombination of V(D)J gene segments of IGH and TCR genes.

NON-TEMPLATED NUCLEOTIDES

(N-nucleotides). Nucleotides that are added at random (by terminal deoxynucleotidyl transferase) to rearranging V(D)J gene segments. This process increases the diversity of B-cell and T-cell receptors.

NON-HOMOLOGOUS END-JOINING

(NHEJ). The main, DNA-PK-dependent mechanism for the repair of double-strand DNA breaks in mammalian cells. It is involved in the response to DNA-damaging agents and physiological V(D)J recombination. NHEJ occurs in the absence of significant homology or a template and is prone to error.

HOMOLOGOUS RECOMBINATION (HR)

A common repair mechanism for DNA breaks that uses repetitive (homologous) sequences (for example, Alu elements or sister chromatids) as templates for repair.

ALU ELEMENT

Part of a family of short, interspersed repeats, Alu sequences are the most abundant sequence repeats in the human genome (comprising 5–10% of the total). Alu sequences can be propagated by retrotransposition, although most are sterile, or DNA 'fossils'.

GUTHRIE CARD

An absorbent card onto which neonatal blood drops are routinely deposited, as spots, and archived for biochemical, immunological or molecular screening.

KNUDSON TWO-STEP MODEL

A model for the development of paediatric cancer involving two discrete but complementary genetic events, the first of which can be either initiated in the germline or acquired somatically, early in life.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greaves, M., Wiemels, J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3, 639–649 (2003). https://doi.org/10.1038/nrc1164

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1164

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing