Acquired abnormalities of chromosome 21 in acute lymphoblastic leukaemia

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

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2008

Author dc:creator

• Robinson, Hazel M.

Advisors dc:contributor.advisor

• Harrison, Christine J.
• Moorman, Anthony