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 leukaemia in children with Down syndrome

Nature Reviews Cancer volume 5, pages 11–20 (2005)Cite this article

Key Points

  • Children with Down syndrome (DS, characterized by constitutional trisomy 21) have a 10–20-fold increased incidence of acute leukaemia. Acute megakaryoblastic leukaemia (AMKL) is particularly prevalent, with an estimated 500-fold increased relative risk compared with the general population.

  • Acute myeloid leukaemia in children with DS occurs at a younger age, is usually AMKL and frequently preceded by a phase of abnormal haematopoietic differentiation (myelodysplastic syndrome) and shows increased sensitivity to chemotherapy.

  • A transient form of megakaryoblastic leukaemia — known as transient leukaemia (TL) — is found in 10% of newborn infants with DS and in most cases resolves spontaneously. However, an estimated 20% of children with DS who recover from TL subsequently develop AMKL within the first 4 years of life.

  • The leukaemic blasts of DS-AMKL harbour somatic mutations of GATA1, which encodes a haematopoietic transcription factor encoded on the X chromosome. Most mutations cluster within exon 2 and result in the expression of a truncated mutant protein, GATA1s, that lacks the amino-terminal transcriptional activation domain.

  • GATA1 mutations are also present in TL blasts detected at birth, indicating that they represent an early event occurring in utero. Concordant GATA1 mutations and cytogenetic abnormalities in TL and DS-AMKL blasts of the same individual support a model in which DS-AMKL arises from a persistent subclone of TL cells as the result of additional, as yet undetermined, mutations.

  • Megakaryoblastic leukaemia that develops on the basis of trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.

Abstract

Transient megakaryoblastic leukaemia is found in 10% of newborns with Down syndrome, characterized by constitutional trisomy 21. Although in most cases the leukaemic cells disappear spontaneously after the first months of life, irreversible acute megakaryoblastic leukaemia develops in 20% of these individuals within 4 years. The leukaemic cells typically harbour somatic mutations of the gene encoding GATA1, an essential transcriptional regulator of normal megakaryocytic differentiation. Leukaemia that specifically arises in the context of constitutional trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Haematopoietic differentiation showing detail of the megakaryocytic pathway.
Figure 2: Abnormal differentiation in megakaryoblastic leukaemia.
Figure 3: Functional domains of GATA1.
Figure 4: Megakaryoblastic leukaemia of Down syndrome — a model of incremental malignant transformation.

Similar content being viewed by others

References

  1. Ross, J. A., Spector, L. G., Robison, L. L. & Olshan, A. F. Epidemiology of leukemia in children with Down syndrome. Pediatr. Blood Cancer 44, 8–12 (2005)

    Article  PubMed  Google Scholar 

  2. Fong, C. T. & Brodeur, G. M. Down's syndrome and leukemia: epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis. Cancer Genet. Cytogenet. 28, 55–76 (1987).

    Article  CAS  PubMed  Google Scholar 

  3. Avet-Loiseau, H., Mechinaud, F. & Harousseau, J. L. Clonal hematologic disorders in Down syndrome. A review. J. Pediatr. Hematol. Oncol. 17, 19–24 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Satge, D. et al. A tumor profile in Down syndrome. Am. J. Med. Genet. 78, 207–216 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Hasle, H., Clemmensen, I. H. & Mikkelsen, M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355, 165–169 (2000). Population-based overview of the frequencies of leukaemic and non-leukaemic malignant disorders in DS highlighting the association with an increased risk of leukaemia and a decreased incidence of solid tumours.

    Article  CAS  PubMed  Google Scholar 

  6. Hasle, H. Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol. 2, 429–436 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Bennett, J. M. et al. Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French–American–British Cooperative Group. Ann. Intern. Med. 103, 460–462 (1985).

    Article  CAS  PubMed  Google Scholar 

  8. Zipursky, A., Poon, A. & Doyle, J. Leukemia in Down syndrome: a review. Pediatr. Hematol. Oncol. 9, 139–149 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Wechsler, J. et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nature Genet. 32, 148–152 (2002). First demonstration that somatic mutations of GATA1 resulting in the expression of a mutant protein truncated at the amino terminus are specific for AMKL of DS.

    Article  CAS  PubMed  Google Scholar 

  10. Lange, B. J. et al. Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 91, 608–615 (1998).

    CAS  PubMed  Google Scholar 

  11. Zipursky, A., Thorner, P., De Harven, E., Christensen, H. & Doyle, J. Myelodysplasia and acute megakaryoblastic leukemia in Down's syndrome. Leuk. Res. 18, 163–171 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Zipursky, A. Transient leukaemia — a benign form of leukaemia in newborn infants with trisomy 21. Br. J. Haematol. 120, 930–938 (2003). Recent review of the clinical, cellular and molecular features of TL as a unique reversible disorder that precedes AMKL in DS.

    Article  PubMed  Google Scholar 

  13. Kurahashi, H. et al. Monoclonal nature of transient abnormal myelopoiesis in Down's syndrome. Blood 77, 1161–1163 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Miyashita, T. et al. Clonal analysis of transient myeloproliferative disorder in Down's syndrome. Leukemia 5, 56–59 (1991).

    CAS  PubMed  Google Scholar 

  15. Shimada, A. et al. Fetal origin of the GATA1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome. Blood 103, 366 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Al-Kasim, F., Doyle, J. J., Massey, G. V., Weinstein, H. J. & Zipursky, A. Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study. J. Pediatr. Hematol. Oncol. 24, 9–13 (2002).

    Article  PubMed  Google Scholar 

  17. Dormann, S. et al. Life-threatening complications of transient abnormal myelopoiesis in neonates with Down syndrome. Eur. J. Pediatr. 163, 374–377 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Tchernia, G. et al. Erythroblastic and/or megakaryoblastic leukemia in Down syndrome: treatment with low-dose arabinosyl cytosine. J. Pediatr. Hematol. Oncol. 18, 59–62 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Zipursky, A., Rose, T., Skidmore, M., Thorner, P. & Doyle, J. Hydrops fetalis and neonatal leukemia in Down syndrome. Pediatr. Hematol. Oncol. 13, 81–87 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Miyauchi, J., Ito, Y., Kawano, T., Tsunematsu, Y. & Shimizu, K. Unusual diffuse liver fibrosis accompanying transient myeloproliferative disorder in Down's syndrome: a report of four autopsy cases and proposal of a hypothesis. Blood 80, 1521–1527 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Gamis, A. S. & Hilden, J. M. Transient myeloproliferative disorder, a disorder with too few data and many unanswered questions: does it contain an important piece of the puzzle to understanding hematopoiesis and acute myelogenous leukemia? J. Pediatr. Hematol. Oncol. 24, 2–5 (2002).

    Article  PubMed  Google Scholar 

  22. Clark, S., Nathan, D. G. & Sieff, C. in Nathan and Oski's Hematology of Infancy and Childhood 6th edn (eds Nathan, D., Orkin, S., Ginsburg, D. & Look, A.) 171–255 (2003).

    Google Scholar 

  23. Israels, S. J., Rand, M. L. & Michelson, A. D. Neonatal platelet function. Semin. Thromb. Hemost. 29, 363–372 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Ma, S. K., Lee, A. C., Wan, T. S., Lam, C. K. & Chan, L. C. Trisomy 8 as a secondary genetic change in acute megakaryoblastic leukemia associated with Down's syndrome. Leukemia 13, 491–492 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Duflos-Delaplace, D. et al. Transient leukemoid disorder in a newborn with Down syndrome followed 19 months later by an acute myeloid leukemia: demonstration of the same structural change in both instances with clonal evolution. Cancer Genet. Cytogenet. 113, 166–171 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Polski, J. M. et al. Acute megakaryoblastic leukemia after transient myeloproliferative disorder with clonal karyotype evolution in a phenotypically normal neonate. J. Pediatr. Hematol. Oncol. 24, 50–54 (2002).

    Article  PubMed  Google Scholar 

  27. Hayashi, Y. et al. Cytogenetic findings and clinical features in acute leukemia and transient myeloproliferative disorder in Down's syndrome. Blood 72, 15–23 (1988).

    Article  CAS  PubMed  Google Scholar 

  28. Ahmed, M. et al. Natural history of GATA1 mutations in Down Syndrome. Blood 103, 2480–2489 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Zipursky, A., Christensen, H. & De Harven, E. Ultrastructural studies of the megakaryoblastic leukemias of Down syndrome. Leuk. Lymphoma 18, 341–347 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Eguchi, M. et al. Ultrastructural and ultracytochemical differences between transient myeloproliferative disorder and megakaryoblastic leukaemia in Down's syndrome. Br. J. Haematol. 73, 315–322 (1989).

    Article  CAS  PubMed  Google Scholar 

  31. Slordahl, S. H. et al. Leukemic blasts with markers of four cell lineages in Down's syndrome ('megakaryoblastic leukemia'). Med. Pediatr. Oncol. 21, 254–258 (1993).

    Article  CAS  PubMed  Google Scholar 

  32. Bozner, P. Transient myeloproliferative disorder with erythroid differentiation in Down syndrome. Arch. Pathol. Lab. Med. 126, 474–477 (2002).

    Article  PubMed  Google Scholar 

  33. Vanhaeke, D., Vainchenker, W., Yver, A. & Leverger, G. [A case of erythoblastic leukemia with basophilic reaction]. Presse Med. 20, 267 (1991).

    CAS  PubMed  Google Scholar 

  34. Ito, E. et al. Expression of erythroid-specific genes in acute megakaryoblastic leukaemia and transient myeloproliferative disorder in Down's syndrome. Br. J. Haematol. 90, 607–614 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Suda, J. et al. Differentiation of blast cells from a Down's syndrome patient with transient myeloproliferative disorder. Blood 69, 508–512 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Suda, T. et al. Clonal analysis of basophil differentiation in bone marrow cultures from a Down's syndrome patient with megakaryoblastic leukemia. Blood 66, 1278–1283 (1985).

    Article  CAS  PubMed  Google Scholar 

  37. Worth, L. L., Zipursky, A., Christensen, H. & Tubergen, D. Transient leukemia with extreme basophilia in a phenotypically normal infant with blast cells containing a pseudodiploid clone, 46,XY i(21)(q10). J. Pediatr. Hematol. Oncol. 21, 63–66 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Cantor, A. B. & Orkin, S. H. Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21, 3368–3376 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Kulessa, H., Frampton, J. & Graf, T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev. 9, 1250–1262 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Orkin, S. H., Shivdasani, R. A., Fujiwara, Y. & McDevitt, M. A. Transcription factor GATA-1 in megakaryocyte development. Stem Cells 16 (Suppl. 2), 79–83 (1998).

    PubMed  Google Scholar 

  41. Tsang, A. P. et al. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 90, 109–119 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Shivdasani, R. A. et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 81, 695–704 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Hart, A. et al. Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity 13, 167–177 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Saleque, S., Cameron, S. & Orkin, S. H. The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev. 16, 301–306 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Matsumura, I. & Kanakura, Y. Molecular control of megakaryopoiesis and thrombopoiesis. Int. J. Hematol. 75, 473–483 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, Q. et al. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. PNAS 93, 3444–3449 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Elagib, K. E. et al. RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation. Blood 101, 4333–4341 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Tsai, S. F. et al. Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature 339, 446–451 (1989).

    Article  CAS  PubMed  Google Scholar 

  50. Evans, T. & Felsenfeld, G. The erythroid-specific transcription factor Eryf1: a new finger protein. Cell 58, 877–885 (1989).

    Article  CAS  PubMed  Google Scholar 

  51. Martin, D. I., Zon, L. I., Mutter, G. & Orkin, S. H. Expression of an erythroid transcription factor in megakaryocytic and mast cell lineages. Nature 344, 444–447 (1990).

    Article  CAS  PubMed  Google Scholar 

  52. Romeo, P. H. et al. Megakaryocytic and erythrocytic lineages share specific transcription factors. Nature 344, 447–449 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. Zon, L. I. et al. Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription. Blood 81, 3234–3241 (1993).

    Article  CAS  PubMed  Google Scholar 

  54. Hirasawa, R. et al. Essential and instructive roles of GATA factors in eosinophil development. J. Exp. Med. 195, 1379–1386 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yu, C. et al. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J. Exp. Med. 195, 1387–1395 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Migliaccio, A. R. et al. GATA-1 as a regulator of mast cell differentiation revealed by the phenotype of the GATA-1low mouse mutant. J. Exp. Med. 197, 281–296 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Visvader, J. E., Elefanty, A. G., Strasser, A. & Adams, J. M. GATA-1 but not SCL induces megakaryocytic differentiation in an early myeloid line. EMBO J. 11, 4557–4564 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yamaguchi, Y., Zon, L. I., Ackerman, S. J., Yamamoto, M. & Suda, T. Forced GATA-1 expression in the murine myeloid cell line M1: induction of c-Mpl expression and megakaryocytic/erythroid differentiation. Blood 91, 450–457 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C. & Orkin, S. H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl Acad. Sci. USA 93, 12355–12358 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shivdasani, R. A., Fujiwara, Y., McDevitt, M. A. & Orkin, S. H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 16, 3965–3973 (1997). Description of the effects of GATA1 deficiency in the cells of megakaryocytic lineage in an in vivo model that has phenotypic similarities with TL of DS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vyas, P., Ault, K., Jackson, C. W., Orkin, S. H. & Shivdasani, R. A. Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 93, 2867–2875 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Gurbuxani, S., Vyas, P. & Crispino, J. D. Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 103, 399–406 (2004). Comprehensive review of currently available models of decreased haematopoietic GATA1 function in vivo and the effects on megakaryocytic differentiation.

    Article  CAS  PubMed  Google Scholar 

  63. Takahashi, S. et al. Role of GATA-1 in proliferation and differentiation of definitive erythroid and megakaryocytic cells in vivo. Blood 92, 434–442 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Vannucchi, A. M. et al. Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1low mice). Blood 100, 1123–1132 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Cripe, L. & Hromas, R. Malignant disorders of megakaryocytes. Semin. Hematol. 35, 200–209 (1998).

    CAS  PubMed  Google Scholar 

  66. Nichols, K. E. et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nature Genet. 24, 266–270 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Freson, K. et al. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98, 85–92 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Mehaffey, M. G., Newton, A. L., Gandhi, M. J., Crossley, M. & Drachman, J. G. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98, 2681–2688 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Yu, C. et al. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 100, 2040–2045 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Crispino, J. D. GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr. Blood Cancer 44, 40–44 (2005).

    Article  PubMed  Google Scholar 

  71. Rainis, L. et al. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102, 981–986 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Hitzler, J. K., Cheung, J., Li, Y., Scherer, S. W. & Zipursky, A. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101, 4301–4304 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Xu, G. et al. Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. Blood 102, 2960–2968 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Harigae, H. et al. The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome. Blood 103, 3242–3243 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Taub, J. W. & Ge, Y. Down syndrome, drug metabolism and chromosome 21. Pediatr. Blood Cancer 44, 33–39 (2005).

    Article  PubMed  Google Scholar 

  76. Ge, Y. et al. The role of cytidine deaminase and GATA1 mutations in the increased cytosine arabinoside sensitivity of Down syndrome myeloblasts and leukemia cell lines. Cancer Res. 64, 728–735 (2004). Update on the unique pharmacological sensitivity of the blasts in (non-lymphoid) leukaemia of DS with reference to previous work in this area.

    Article  CAS  PubMed  Google Scholar 

  77. Groet, J. et al. Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 361, 1617–1620 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Mundschau, G. et al. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101, 4298–4300 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Taub, J. W. et al. Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. Blood 104, 1588–1589 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Rylski, M. et al. GATA-1-mediated proliferation arrest during erythroid maturation. Mol. Cell. Biol. 23, 5031–5042 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. McElwaine, S. et al. Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker. Br. J. Haematol. 125, 729–742 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Lightfoot, J., Hitzler, J., Zipursky, A., Albert, M. & Macgregor, P. Distinct gene signatures of transient and acute megakaryoblastic leukemia in Down syndrome. Leukemia 18, 1617–1623 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Calligaris, R., Bottardi, S., Cogoi, S., Apezteguia, I. & Santoro, C. Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. Proc. Natl Acad. Sci. USA 92, 11598–11602 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shimizu, R., Takahashi, S., Ohneda, K., Engel, J. D. & Yamamoto, M. In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis. EMBO J. 20, 5250–5260 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  86. Ichikawa, M. et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nature Med. 10, 299–304 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Song, W. J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genet. 23, 166–175 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Waltzer, L., Ferjoux, G., Bataille, L. & Haenlin, M. Cooperation between the GATA and RUNX factors Serpent and Lozenge during Drosophila hematopoiesis. EMBO J. 22, 6516–6525 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gilliland, D. G. & Tallman, M. S. Focus on acute leukemias. Cancer Cell 1, 417–420 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Izraeli, S. Leukaemia — a developmental perspective. Br. J. Haematol. 126, 3–10 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Hattori, M. et al. The DNA sequence of human chromosome 21. Nature 405, 311–319 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Antonarakis, S. E., Lyle, R., Dermitzakis, E. T., Reymond, A. & Deutsch, S. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nature Rev. Genet. 5, 725–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Gitton, Y. et al. A gene expression map of human chromosome 21 orthologues in the mouse. Nature 420, 586–590 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Reymond, A. et al. Human chromosome 21 gene expression atlas in the mouse. Nature 420, 582–586 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Korenberg, J. R. et al. Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc. Natl Acad. Sci. USA 91, 4997–5001 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kola, I. & Hertzog, P. J. Down syndrome and mouse models. Curr. Opin. Genet. Dev. 8, 316–321 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Epstein, C. J., Cox, D. R. & Epstein, L. B. Mouse trisomy 16: an animal model of human trisomy 21 (Down syndrome). Ann. NY Acad. Sci. 450, 157–168 (1985).

    Article  CAS  PubMed  Google Scholar 

  98. Roizen, N. J. & Patterson, D. Down's syndrome. Lancet 361, 1281–1289 (2003).

    Article  PubMed  Google Scholar 

  99. Jones, K. Smith's Recognizable Patterns of Human Malformation 4th edn 10–15 (W. B. Saunders Company, Philadelphia, 1988).

    Google Scholar 

  100. Down, J. Observations on an ethnic classification of idiots. London Hosp. Clin. Lect. Rep. 259 (1866).

  101. Lejeune, J., Gautier, M. & Turpin, R. Etude des chromosomes somatiques de neuf enfants mongoliens. C.R. Acad. Sci. 248, 1721–1722 (1959).

    CAS  Google Scholar 

  102. Ravindranath, Y. Down syndrome and acute myeloid leukemia: the paradox of increased risk for leukemia and heightened sensitivity to chemotherapy. J. Clin. Oncol. 21, 3385–3387 (2003).

    Article  PubMed  Google Scholar 

  103. Ravindranath, Y. et al. Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 80, 2210–2214 (1992).

    Article  CAS  PubMed  Google Scholar 

  104. Gamis, A. S. et al. Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J. Clin. Oncol. 21, 3415–3422 (2003).

    Article  PubMed  Google Scholar 

  105. Taub, J. W. et al. Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood 94, 1393–1400 (1999).

    CAS  PubMed  Google Scholar 

  106. Taub, J. W. et al. Enhanced metabolism of 1-β-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 87, 3395–3403 (1996).

    Article  CAS  PubMed  Google Scholar 

  107. Zipursky, A. The treatment of children with acute megakaryoblastic leukemia who have Down syndrome. J. Pediatr. Hematol. Oncol. 18, 10–12 (1996).

    Article  Google Scholar 

  108. Arai, H. et al. Immunohistochemical study on transforming growth factor-β1 expression in liver fibrosis of Down's syndrome with transient abnormal myelopoiesis. Hum. Pathol. 30, 474–476 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Hattori, H. et al. High expression of platelet-derived growth factor and transforming growth factor-β1 in blast cells from patients with Down Syndrome suffering from transient myeloproliferative disorder and organ fibrosis. Br. J. Haematol. 115, 472–475 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Greaves, M. F. & Wiemel, J. Origins of chromosome translocations in childhood leukaemia. Nature Rev. Cancer 3, 639–649 (2003).

    Article  CAS  Google Scholar 

  111. Trainor, C. D. et al. A palindromic regulatory site within vertebrate GATA-1 promoters requires both zinc fingers of the GATA-1 DNA-binding domain for high-affinity interaction. Mol. Cell. Biol. 16, 2238–2247 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hasle, H. et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17, 277–282 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Creutzig, U. et al. Myelodysplasia and acute myelogenous leukemia in Down's syndrome. A report of 40 children of the AML-BFM study group. Leukemia 10, 1677–1686 (1996).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful for the technical assistance of E. J. Brown and H. Christensen.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Johann K. Hitzler & Alvin Zipursky

  2. Program in Developmental Biology, The Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada

    Johann K. Hitzler

Authors
  1. Johann K. Hitzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alvin Zipursky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johann K. Hitzler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

CDKN2C

FLI1

FOG1

GATA1

GFI1B

MYCN

NF-E2

RUNX1

National Cancer Institute

acute lymphoblastic leukaemia

acute myeloid leukaemia

OMIM

Down syndrome

Glossary

TRISOMY

Presence of three copies of a chromosome per cell; in the case of constitutional trisomy, all cells of an organism are affected.

BLAST

Immature white cell representing the predominant (clonal) cell population that accumulates in leukaemia.

MEGAKARYOCYTE

Principal cell of the megakaryocytic lineage in normal bone marrow that is characterized by a large amount of cytoplasm and multiple nuclear lobes (resulting from endomitosis); the megakaryocyte is the immediate precursor to platelets.

NON-DISJUNCTION

Lack of the physiological separation of the two copies of each chromosome during cell division.

MATERNAL MEIOSIS

Reductive cell division in cells of the ovary that results in the production of mature haploid (containing only a single copy of each chromosome) egg cells.

MAST CELL

Bone-marrow-derived cell type that, like basophils, is defined by staining properties with basic dyes; cytoplasmic granules contain histamine and chemical mediators implicated in inflammatory and immunological processes.

FAMILIAL DYSERYTHROPOIETIC ANAEMIA

Rare inherited blood disorder defined by the lack of red cells in the blood and the presence of abnormally shaped red blood cell precursors in the bone marrow (dyserythropoiesis).

THROMBOCYTOPAENIA

Condition of a decreased platelet count in the blood; if marked, this condition results in an increased risk of bleeding.

THALASSAEMIA

Inherited blood disorder defined by lack of red cells due to impaired or absent synthesis of haemoglobin chains.

HAPLOINSUFFICIENCY

A situation in which a loss-of-function phenotype is produced by mutating one allele of a gene in a diploid cell, even though the other allele is wild type.

MOSAICISM

Presence in one individual of two or more cell populations of different chromosomal constitution that are derived from a single zygote.

SYNTENIC

Corresponding — in a second species — to the observed grouping of genes on the same chromosome in one species.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hitzler, J., Zipursky, A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer 5, 11–20 (2005). https://doi.org/10.1038/nrc1525

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1525

This article is cited by

Search

Advanced 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