Acquired abnormalities of chromosome 21 in acute lymphoblastic leukaemia

Abstract

The intrachromosomal amplification of chromosome 21 (iAMP21) was identified
as a novel and prognositically important acquired chromosomal abnormality in
childhood acute lymphoblastic leukaemia (ALL). It is defined by multiple copies
of the RUNX1 gene, as seen by fluorescence in situ hybridisation (FISH), localised
to a single abnormal duplicated chromosome 21 [dup(21)]. The morphological
form of this chromosome is highly variable between patients and currently the
only reliable method of detection is FISH with probes to RUNX1. Studies of 48
iAMP21 patients using detailed FISH techniques and array-based comparative
genomic hybridisation highlighted an extensive region of chromosome 21
involvement. A minimum common region of amplification, between 33.19 and
39.80Mb, including RUNX1 was identified, together with a minimum common
region of deletion, between 46.54 and 46.92Mb, in 100% and 77% of patients,
respectively. This study established that there were unique patterns of imbalance,
with evidence of deletions, inversions and amplification, displayed on the
dup(21), between individual patients. This provided evidence of an abnormality
that may have arisen from a breakage-fusion-bridge mechanism, possibly initiated
by loss of a telomere. Results indicated that iAMP21 represents a distinct genetic
subgroup of childhood ALL and is not secondary to a cryptic abnormality of
chromosome 21. Two possible variant cases were identified both involving
chromosome 15. The abnormality can be distinguished from other numerical
abnormalities of chromosome 21 by exploiting the unique pattern of gain,
amplification and deletion seen in these patients. This allowed for the
development of diagnostic tests based on copy number using either FISH or
multiplex ligation dependent probe amplification (MLPA), both of which
successfully identified iAMP21 patients.

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