Elsevier

Early Human Development

Volume 82, Issue 12, December 2006, Pages 767-773
Early Human Development

Down myeloid disorders: A paradigm for childhood preleukaemia and leukaemia and insights into normal megakaryopoiesis

https://doi.org/10.1016/j.earlhumdev.2006.09.016Get rights and content

Abstract

Newborns and children with Down Syndrome are predisposed to a range of blood disorders, which include acute lymphoblastic leukaemia and acute megakaryocytic leukaemia (AMKL). Over the last four years there has been considerable progress in our understanding of DS AMKL. Like other childhood leukaemias DS AMKL is initiated in utero and can present in the neonatal period as a clinically overt preleukaemic condition, transient myeloproliferative disorder (TMD). In addition to trisomy 21, fetal haemopoietic progenitors acquire N-terminal truncating mutations in the key megakaryocyte-erythroid transcription factor GATA1. These are the minimum required events for TMD to develop. In ∼ 30% of TMD patients, additional as yet unidentified (epi)genetic mutations are required for progression to AMKL. Thus, DS TMD and AMKL provide a unique model of childhood leukaemia where the preleukaemic and leukaemic phases are ascertainable and separable allowing distinct steps in leukaemogenesis to be studied individually. These findings also have implications for the clinical management of DS TMD and AMKL specifically and also of childhood leukaemia more generally.

Introduction

Down Syndrome is one of the commonest congenital disorders affecting 1/800–1000 live births. It has been known for four to five decades that neonates and children with Down Syndrome are uniquely predisposed to leukaemia. Population- and cancer registry-based studies have shown that children and neonates with Down Syndrome have a 10–20-fold increased risk of developing leukaemia overall despite not being cancer prone in general (see Ref. [1] and references therein). Moreover, deaths from leukaemia, in part, account for the excess mortality associated with the diagnosis of Down Syndrome [2].

Children with Down Syndrome develop both acute lymphoblastic leukaemia (ALL) (which is much more common in the general paediatric population) and acute myeloid leukaemia (AML). DS children have a 33-fold greater increased incidence of ALL. The clinical and molecular features of ALL are similar in DS and non-DS children, although in general, the outcome for children with DS ALL is less good than for non-DS children with ALL.

In contrast, the spectrum of AML in the first five years of life is markedly distinct from AML that develops in non-DS children. Neonates with Down Syndrome can present with a clonal myeloid preleukaemic illness of the megakaryocyte/red cell lineages, alternatively termed transient myeloproliferative disorder (TMD), transient abnormal myelopoiesis (TAM) and transient leukaemia (TL). ∼ 20% of infants with this disorder progress to a sub-type of AML of the megakaryocytic/erythroid lineage termed acute megakaryocytic leukaemia (AMKL or AML M7) (Fig. 1a). Overall, children with DS are 150-fold more likely to develop AML and ∼ 500-fold more likely AMKL, which is rare in non-DS children.

Over the last four years our understanding of the molecular and cellular biology of these disorders has moved forward apace with the impetus provided by the discovery that virtually all cases of TMD and AMKL are characterised by a mutation in the key megakaryocyte-erythroid transcription factor GATA1. There is now clear evidence that TMD and AMKL are linked conditions, with TMD the preleukaemic phase of AMKL. Here, recent advances in TMD and AMKL are reviewed.

Section snippets

DS TMD

Though not often mentioned in general reviews on Down Syndrome and on national Down Syndrome Association websites in the UK and USA, abnormalities in the blood count are not uncommon in newborn babies with Down Syndrome. Haematological abnormalities in neonates with DS include polycythaemia, thrombocytopenia and TMD; these abnormalities can also occur in mosaic DS (reviewed in Ref. [3]). TMD has a variable clinical presentation. In a recent prospective survey of 48 TMD cases over a 3-year

GATA1 function in normal megakaryocyte and red cell

GATA1 was one of the first haemopoietic transcription factors to be cloned. Over the last two decades a large body of work has established its critical role in regulating megakaryocyte and erythroid maturation from multi-potential myeloid progenitors that has been conserved through evolution (reviewed in Ref. [9]. GATA1 is a double zinc finger DNA-binding transcription factor principally expressed in haematopoietic cells. It promotes specification and terminal maturation of myeloid progenitor

Significance of fetal haemopoiesis

The origin of DS AMLKL in the fetus is consistent findings from other childhood leukaemias (reviewed in Ref. [18]). Clinically, this would explain the observation that DS AMKL is not seen in children above 4 years of age (presumably if the oncogenic mutations have not occurred by then the preleukaemic clone is extinguished). It also would explain the fact that though adults develop AML where trisomy of Hsa21 is part of the karyotype of the leukaemic clone, GATA1 mutations are not detected and

Understanding the role of Trisomy 21

An important and complex issue is the role of gene dosage of Hsa21 encoded protein and non-protein encoding genes. Multiple genes may be involved and the effect on fetal haemopoiesis needs to be ascertained. The effects may either be primarily on blood cells or be secondary via other cell types and may be exerted indirectly via disomic genes. These complexities of understanding how a trisomic state impacts on biology are well set out in a recent review [19]. To understand fetal biology and to

Additional events for leukaemic progression from TMD to AMKL

One area of research interest is to identify the additional (epi)genetic events that lead to progression of TMD and AMKL. Over the last two years a number of potential candidate genes have emerged. The most important of these is a recent report of mutation of the signalling molecule JAK3, which have been described in 2/19 patients with AMKL [22]. The mutation is of importance and is reminiscent of mutations in the JAK2 gene in adult megakaryocyte myeloproliferative disorders. However, it is too

TMD and AMKL: a multi-step model of leukaemogenesis

Taken together these findings would suggest that there are at least three distinct pathogenetic steps in DS AMKL. First, a fetal haemopoietic cell would have to be trisomic for chromosome 21. The importance of trisomy is underscored by rare cases of TMD in non-DS neonates [23]. In all cases studied the TMD clone had acquired an additional chromosome 21 (Hsa21). There is one exception to this of a non-DS patient with relapsed AMKL who had an exon 2 GATA1 mutation. The second event required for

Summary

DS TMD and AMKL are unique paired clonal myeloid preleukaemic and leukaemic disorders that arrest megakaryocyte-erythroid differentiation. These conditions provide a powerful model to understand general principles of leukaemogenesis as both the preleukaemic and leukaemic conditions are easily ascertainable; two of the key genetic events (trisomy 21 and mutation of GATA1) are known; and the tools to dissect perturbed megakaryocyte and erythroid differentiation in these disorders are available.

Acknowledgements

The requirement of brevity and restrictions on the number of references the review has meant a substantial amount of important work and references have been omitted. These omissions in no way reflect on the quality and importance of the research in these areas.

PV is a Wellcome Trust Senior Clinical Fellow and is funded by the Wellcome Trust, Leukaemia Research Fund and the Medical Research Council. IR is funded by the Kay Kendall Fund.

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