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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kersey, J. H. Fifty years of studies of the biology and therapy of childhood leukemia. Blood 90, 4243–4251 (1997).
Biondi, A., Cimino, G., Pieters, R. & Pui, C. -H. Biological and therapeutic aspects of infant leukemia. Blood 96, 24–33 (2000).
Raimondi, S. C. in Childhood Leukemias. (ed. Pui, C.-H.) 168–196 (Cambridge Univ. Press, Cambridge, 1999).
Look, A. T. Oncogenic transcription factors in the human acute leukemias. Science 278, 1059–1064 (1997).
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.
Armstrong, S. A. et al. MLL translocations specify a distinct gene expression profile, distinguishing a unique leukemia. Nature Genet. 30, 41–47 (2002).
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).
Rabbitts, T. H. Chromosomal translocations in human cancer. Nature 372, 143–149 (1994).
Rowley, J. D. The critical role of chromosome translocations in human leukemias. Annu. Rev. Genet. 32, 495–519 (1998).
Lengauer, C. How do tumors make ends meet? Proc. Natl Acad. Sci. USA 98, 12331–12333 (2001).
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).
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.
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).
Enver, T. & Greaves, M. Loops, lineage, and leukemia. Cell 94, 9–12 (1998).
Tenen, D. G. Disruption of differentiation in human cancer: AML shows the way. Nature Rev. Cancer 3, 89–101 (2003).
Speck, N. A. & Gilliland, D. G. Core-binding factors in haematopoiesis and leukaemia. Nature Rev. Cancer 2, 502–513 (2002).
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).
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).
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).
Xiao, Z. et al. Molecular characterization of genomic AML1-ETO fusions in childhood leukemia. Leukemia 15, 1906–1913 (2001).
Wiemels, J. L. et al. Microclustering of TEL-AML1 translocation breakpoints in childhood acute lymphoblastic leukemia. Genes Chromosom. Cancer 29, 219–228 (2000).
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).
Khanna, K. K. & Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nature Genet. 27, 247–254 (2001).
Chu, G. Double strand break repair. J. Biol. Chem. 272, 24097–24100 (1997).
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).
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).
Küppers, R. & Dalla–Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).
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).
van der Reijden, B. A. et al. Genomic acute myeloid leukemia-associated inv(16)(p13q22) breakpoints are tightly clustered. Oncogene 18, 543–550 (1999).
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).
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).
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).
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).
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).
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).
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).
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).
Wang, J. C. DNA topoisomerases. Annu. Rev. Biochem. 65, 635–692 (1996).
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).
Felix, C. A. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim. Biophys. Acta 1400, 233–255 (1998).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
Rowley, J. D. Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Res. 44, 3159–3168 (1984).
McCulloch, E. Stem cells in normal and leukemic hemopoiesis. Blood 62, 1–13 (1983).
Greaves, M. Cancer. The Evolutionary Legacy (Oxford Univ. Press, Oxford, 2000).
Pierce, G. B., Shikes, R. & Fink, L. M. Cancer: A Problem of Developmental Biology (Prentice Hall Inc, New Jersey, 1978).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Weissman, I. L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157–168 (2000).
Fuchs, E. & Segre, J. A. Stem cells: a new lease on life. Cell 100, 143–155 (2000).
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).
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.
Barr, F. G. Translocations, cancer and the puzzle of specificity. Nature Genet. 19, 121–124 (1998).
Griffiths, S. D. et al. Clonal characteristics of acute lymphoblastic cells derived from BCR/ABL p190 transgenic mice. Oncogene 7, 1391–1399 (1992).
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).
Greaves, M. F. Stem cell origins of leukaemia and curability. Br. J. Cancer 67, 413–423 (1993).
Greaves, M., Maia, A. T., Wiemels, J. L. & Ford, A. M. Leukemia in twins: lessons in natural history. Blood (in the press).
Senator, H. Zur Kenntniss der Leukämie und Pseudoleukämie im Kindesalter. Berliner Klinische Wochenschrift 35, 533–536 (1882).
Clarkson, B. & Boyse, E. A. Possible explanation of the high concordance for acute leukaemia in monozygotic twins. Lancet 1, 699–701 (1971).
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.
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).
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).
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).
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).
Maia, A. T. et al. Molecular tracking of leukemogenesis in a triplet pregnancy. Blood 98, 478–482 (2001).
Ford, A. M. et al. Monoclonal origin of concordant T-cell malignancy in identical twins. Blood 89, 281–285 (1997).
Maia, A. T. et al. Pre-natal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia (in the press).
Greaves, M. Molecular genetics, natural history and the demise of childhood leukaemia. Eur. J. Cancer 35, 173–185 (1999).
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.
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.
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).
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).
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).
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).
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).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
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.
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).
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.
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).
Deininger, M. W. N., Goldman, J. M. & Melo, J. V. The molecular biology of chronic myeloid leukaemia. Blood 96, 3343–3356 (2000).
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).
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).
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).
Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).
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).
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).
Ford, A. M. et al. Origins of 'late' relapse in childhood acute lymphoblastic leukemia with TEL-AML1 fusion genes. Blood 98, 558–564 (2001).
Van Rompaey, L., Potter, M., Adams, C. & Grosveld, G. Tel induces a G1 arrest and suppresses Ras-induced transformation. Oncogene 19, 5244–5250 (2000).
Lopez, R. G. et al. TEL is a sequence-specific transcriptional repressor. J. Biol. Chem. 274, 30132–30138 (1999).
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).
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).
Gilliland, D. G. & Griffin, J. D. The roles of FLT3 in hematopoiesis and leukemia. Blood 100, 1532–1542 (2002).
Knudson, A. G. Stem cell regulation, tissue ontogeny, and oncogenic events. Semin. Cancer Biol. 3, 99–106 (1992).
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).
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).
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.
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).
Szczepanski, T. & van Dongen, J. J. M. in Leukemia (eds. Henderson, E. S., TA, L. & Greaves, M. F.) 249–283 (Saunders, Philadelphia, 2002).
Fenaux, P., Chomienne, C. & Degos, L. Treatment of acute promyelocytic leukaemia. Best Pract. Res. Clin. Haematol. 14, 153–174 (2001).
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.
Redner, R. L., Wang, J. & Liu, J. Chromatin remodeling and leukemia: new therapeutic paradigms. Blood 94, 417–428 (1999).
Rabbitts, T. H. & Stocks, M. R. Chromosomal translocation products engender new intracellular therapeutic technologies. Nature Med. 9, 383–386 (2003).
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).
Greaves, M. F. Aetiology of acute leukaemia. Lancet 349, 344–349 (1997).
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).
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).
Alexander, F. E. et al. Transplacental chemical exposure and risk of infant leukaemia with MLL gene fusion. Cancer Res. 61, 2542–2546 (2001).
Ma, X. et al. Daycare attendance and risk of childhood acute lymphoblastic leukaemia. Br. J. Cancer 86, 1419–1424 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
Greaves, M. F. Differentiation-linked leukaemogenesis in lymphocytes. Science 234, 697–704 (1986).
Ridge, S. A. et al. Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement. Leukemia 9, 2023–2026 (1995).
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).
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).
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).
Kempski, H. et al. Prenatal chromosomal diversification of leukemia in monozygotic twins. Genes Chromosom. Cancer 37, 406–411 (2003).
Acknowledgements
M.G. is supported by a specialist programme grant from the Leukaemia Research Fund, UK.
Author information
Authors and Affiliations
Corresponding author
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
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
Issue Date:
DOI: https://doi.org/10.1038/nrc1164
This article is cited by
-
Effects of low-dose ionizing radiation on genomic instability in interventional radiology workers
Scientific Reports (2023)
-
The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation
Cell Death & Disease (2023)
-
Evolutionary determinants of curability in cancer
Nature Ecology & Evolution (2023)
-
Is neonatal phototherapy associated with a greater risk of childhood cancers?
BMC Pediatrics (2022)
-
Consanguinity and childhood acute lymphoblastic leukaemia: a case-control study
Egyptian Pediatric Association Gazette (2022)