Down's Syndrome—Transient Abnormal Myelopoiesis and Acute Leukaemia

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Abstract
Subjects with Down's syndrome have an increased risk, particularly during childhood, of developing acute leukaemia. There is an increased incidence both of acute lymphoblastic leukaemia and of acute myeloid leukaemia (AML), particularly acute megakaryoblastic leukaemia, often presenting with the clinical features of acute myelofibrosis. In addition neomates with Down's syndrome show a high incidence of polycythaemia and may also develope a syndrome simulating acute leukaemia, commonly designated transient abnormal myelopoiesis (TAM). Although TAM closely resembles acute leukaemia there are some subtle differences and infants who survive four to eight weeks usually show a complete remission. Subsequently a significant proportion of these infants develop AML usually around the age of 2 to 3 years. Cytogenetic evidence indicates that in at least some neonates with TAM the abnormal cells are monoclonal. The presence of a cytogenetically abnormal clone is not incompatible with subsequent complete remission with loss of the abnormal close and long survival. For these reasons it may be justifiable to regard TAM as transient acute myeloid leukaemia. Although other lineages are also involved in TAM the blast cells are usually predominantly megakaryoblasts. This, together with the predominance of megakaryoblastic leukaemia among cases of AML in Down's syndrome, suggests that abnormal proliferation of megakaryoblasts in specifically linked to the presence of a supernumerary chromosome 21. Further support for this hypothesis is provided by cases of TAM in subjects with mosaicism for trisomy 21 or for a related abnormality of chromosome 21; the abnormal proliferating cells are derived from the cytogenetically abnormal population. Additional factors are clearly necessary for the occurrence of TAM or AML in subjects with Down's syndrome but their nature is as yet unknown.