Blackburn, Nicola; (2003) Structural abnormalities of chromosome 21 in acute leukaemia and transient abnormal myelopoiesis associated with Down syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Down syndrome (DS) is associated with a 10-15 fold increased risk of developing acute leukaemia (AL). Neonates who have DS or who are mosaic for trisomy of chromosome 21 are predisposed to the development of transient abnormal myelopoiesis (TAM). TAM mimics leukaemia but is characterised by spontaneous resolution within 1-3 months of life. However, the disorder can return in the form of an overt leukaemia in infancy. In the rare cases where a neonate with a normal constitutional karyotype develops TAM, the blast cells show gain of chromosome 21. The relationship between chromosome 21 and haematological disorders is unknown although chromosome 21 harbours the RUNX1 gene (21q22), which is known to be involved in rearrangements associated with leukaemia and to be mutated in disorders that increase the likelihood of developing AL. In this study, Fluorescent In Situ Hybridisation (FISH) and molecular analyses were used to investigate the long arm of chromosome 21 in four children with DS and acute leukaemia, one non-DS child with acute leukaemia and a clonal abnormality involving chromosome 21, seven DS neonates with TAM, and two non-DS neonates with TAM. Interstitial deletions and rearrangements of 21q22-qter were detected in leukaemic cells from 3/4 DS AL cases and in the non-DS AL case, in metaphase cells from 7/7 DS TAM cases and in karyotypically abnormal cells from 2/2 non-DS TAM cases. The RUNX1 gene was partially lost in 4/7 DS TAM cases but was not altered in the DS AL cases. One of the non-DS TAM cases was previously found to show a partial relocation of the RUNX1 gene to the paracentromeric region. On further analysis using clones isolated from a human genome library this region was defined as 21q11.2, which harbours the pseudogenes OR4K11P and OR4K12P. The rearrangements detected were acquired secondarily to the cytogenetic changes found in the DS AL and non-DS TAM cases. This suggests that the submicroscopic alterations may be later events occurring during the progression of the haematological abnormalities in both the DS AL and DS/non-DS TAM patients and may reflect the accumulation of DNA damage.

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