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  • Review Article
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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.

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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.

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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
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  2. Alvin Zipursky
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Correspondence to Johann K. Hitzler.

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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.

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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

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