Origins of leukaemia in children with Down syndrome

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. 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.