Acute Leukemias in Children with Down Syndrome

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Children with Down syndrome have an increased risk for developing both acute myeloid as well as lymphoblastic leukemia. These leukemias differ in presenting characteristics and underlying biology when compared with leukemias occurring in non-Down syndrome children. Myeloid leukemia in children with Down syndrome is preceded by a preleukemic clone (transient leukemia or transient myeloproliferative disorder), which may disappear spontaneously, but may also need treatment in case of severe symptoms. Twenty percent of children with transient leukemia subsequently develop myeloid leukemia. This transition offers a unique model to study the stepwise development of leukemia and of gene dosage effects mediated by aneuploidy.

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Hematologic abnormalities in children with Down syndrome

Tunstall-Pedoe and colleagues15 studied hematopoiesis in fetal bood, bone marrow, and liver cells from 16 fetuses with DS with a gestational age of 15 to 37 weeks. GATA1 mutations were not detected in the hematopoietic cells of these fetuses, although minor clones may have been missed, as explained later in this article. A marked increase in the megakaryocyte-erythrocyte progenitors in the fetal liver was found, as well as dysmegakaryopoiesis and dyserythropoiesis in the peripheral blood, but

How frequent is transient leukemia in Down syndrome children?

The frequency of TL is estimated to be around 10% in DS children, although this was studied in a selected (hospitalized) population.18 Most investigators assume that the true frequency is higher, but recent data suggest that his may not be the case. In The Netherlands, children with DS are registered in different nation-wide registries (the Dutch Pediatric Surveillance Unit and the National Dutch Neonatal and Obstetrical Registry), which provide population-based data. After matching these

Down syndrome transient leukemia: clinical presentation

Massey and colleagues7 recently published the clinical data of a Children's Oncology Group (COG) retrospective study in which 48 neonates with TL were enrolled. The median age at diagnosis of TL was 7 days (range 1–65 days). Approximately 25% of patients were a-symptomatic, although this study may have been biased toward registration of symptomatic patients. Hepatosplenomagaly (in 56% of cases), effusions (in 21%), and bleeding or petechiae (in 25%) were the most common findings in symptomatic

Myeloid Leukemia of Down Syndrome: Clinical Characteristics and Classification

According to the World Health Organization (WHO) classification, AML requires the presence of at least 20% blasts in the bone marrow or peripheral blood.24 However, the pediatric literature suggests that this 20% threshold does not apply to ML in patients with DS.25 Overt leukemia in these children is preceded in 20% to 60% of cases by an indolent prephase of myelodysplasia (MDS), characterized by thrombocytopenia and dysplastic changes in the bone marrow, often with accompanying marrow

Increased risk for toxicity in children with Down syndrome

In children with DS, there is a delicate balance between the antileukemic efficacy of intensive chemotherapy and the increased toxic morbidity and mortality rates with which chemotherapy in these vulnerable children is associated.12, 13, 14, 29, 30 Given the enhanced sensitivity of myeloid leukemic cells in these patients, dose-reductions in ML regimens for DS patients are easier accepted than for ALL regimens. For instance, in the CCG 2891 AML study, excessive toxicity resulted in poor

GATA1 mutations

GATA1 is a double zinc finger DNA-binding transcription factor that has a critical role in promoting specification and terminal maturation of myeloid progenitor cells to red cells and megakaryocytes, that has been conserved through evolution.60 Acquired mutations in the hemopoietic transcription factor GATA1 in ML DS were initially described by Wechsler and colleagues,61 and subsequently by a number of groups. Three studies have studied the function of N-terminal region of GATA1 in murine

Cooperating genetic events involved in progression from transient leukemia to myeloid leukemia of Down syndrome

AML is hypothesized to result from at least two types of cooperating genetic events, including growth promoting mutations (referred to as type 1 genetic aberrations) in, for example, receptor tyrosine kinases (such as FLT3 or KIT) or the RAS-oncogene, as well as translocations—such as t(8;21) or t(15;17)—that mainly impair differentiation (type 2 abnormalities).72 In agreement with this hypothesis, recent studies have shown that GATA1s is insufficient to induce leukemia without other

Summary

Constitutional trisomy 21 results in an enhanced risk of developing leukemias, both ALL as well as ML DS. TL and ML DS offer a unique model to obtain insight into the stepwise progression of leukemia, and of gene dosage effects mediated by aneuploidy. TL arises from expanded fetal liver progenitors as a result of constitutional trisomy 21, providing a window of opportunity for the occurrence of acquired mutations in the hematopoietic transcription factor GATA1. Many questions, however, remain

References (83)

  • Y. Ravindranath et al.

    Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498

    Blood

    (1992)
  • C.M. Zwaan et al.

    Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells, in children with and without Down syndrome

    Blood

    (2002)
  • J.W. Taub et al.

    Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia

    Blood

    (1996)
  • J.W. Taub 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

    (1999)
  • S.R. Pine et al.

    GATA1 as a new target to detect minimal residual disease in both transient leukemia and megakaryoblastic leukemia of Down syndrome

    Leuk Res

    (2005)
  • H. Hasle et al.

    WT1 gene expression in children with Down syndrome and transient myeloproliferative disorder

    Leuk Res

    (2006)
  • M.L. Garré et al.

    Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia

    J Pediatr

    (1987)
  • D. Becton et al.

    Randomized use of Cyclosporin A (CSA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group study 9421

    Blood

    (2006)
  • A.G. Muntean et al.

    Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development

    Blood

    (2005)
  • J.K. Hitzler et al.

    GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome

    Blood

    (2003)
  • G. Mundschau et al.

    Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis

    Blood

    (2003)
  • L. Rainis et al.

    Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21

    Blood

    (2003)
  • J. Groet et al.

    Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder

    Lancet

    (2003)
  • G. Xu et al.

    Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome

    Blood

    (2003)
  • M. Ahmed et al.

    Natural history of GATA1 mutations in Down syndrome

    Blood

    (2004)
  • A. Shimada et al.

    Fetal origin of the GATA1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome

    Blood

    (2004)
  • J.W. Taub et al.

    Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome

    Blood

    (2004)
  • D.K. Walters et al.

    Activating alleles of JAK3 in acute megakaryoblastic leukemia

    Cancer Cell

    (2006)
  • A. Norton et al.

    Analysis of JAK3, JAK2, and C-MPL mutations in transient myeloproliferative disorder and myeloid leukemia of Down syndrome blasts in children with Down syndrome

    Blood

    (2007)
  • T. Mercher et al.

    JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model

    Blood

    (2006)
  • S. Izraeli et al.

    Trisomy of chromosome 21 in leukemogenesis

    Blood Cells Mol Dis

    (2007)
  • W. Krivit et al.

    The simultaneous occurrence of leukemia and mongolism; report of four cases

    AMA J Dis Child

    (1956)
  • J.K. Hitzler et al.

    Origins of leukaemia in children with Down syndrome

    Nat Rev Cancer

    (2005)
  • Z. Li et al.

    Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1

    Nat Genet

    (2005)
  • F. Al Kasim et al.

    Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study

    J Pediatr Hematol Oncol

    (2002)
  • P. Vyas et al.

    Molecular insights into Down syndrome-associated leukemia

    Curr Opin Pediatr

    (2007)
  • M. Bassal et al.

    Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952

    Pediatr Blood Cancer

    (2005)
  • U. Creutzig et al.

    AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity

    Leukemia

    (2005)
  • A.S. Gamis 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

    (2003)
  • O. Tunstall-Pedoe et al.

    Trisomy 21 expands the megakaryocyte-erytroid progenitor compartment in human fetal liver—implications for Down syndrome AMKL

    Blood

    (2006)
  • E. Henry et al.

    Hematological abnormalities during the first week of life among neonates with Down syndrome: data from a multihospital healthcare system

    Am J Med Genet A

    (2007)

    • Cited by (0)

    A version of this article was previously published in the Pediatric Clinics of North America, 55:1.

    None of the authors have direct financial interests to disclose. P. Vyas receives research support from the Leukemia Research Fund; C.M. Zwaan receives research support from Stichting Kinderen Kankervrij.

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