Clonal diversity of ig and T-cell receptor gene rearrangements in childhood B-Precursor acute lymphoblastic leukaemia

The majority of paediatric B precursor acute lymphoblastic leukaemias in ch ildren are derived from a single transformed haematopoietic cell with compl ete or partial VDJ recombination within the immunoglobulin heavy chain gene . A high frequency of patients also show rearrangements within TCR delta an d TCR gamma loci and in up to 40% of children there is an excess of immune system gene rearrangements compared with the number of identified alleles o f immune system genes, suggesting the presence of multiple leukaemic subclo nes -clonal diversity. It has been observed by us and other investigators that in individual patie nts the pattern of immune system gene rearrangements often changes between presentation and relapse. In order to explore the possibility that clonal d iversity plays a biological role during disease progression we optimised me thods for subclone detection and analysed the prognostic significance of cl onal diversity among 75 children with B precursor-ALL. Our results suggest that clonal diversity plays a role in disease progression as patients with oligoclonal disease showed a significantly shorter disease free survival th an patients with monoclonal disease. This trend was of particular importanc e in the 'standard risk' group of ALL where aggressive disease could not be recognised by other means. In addition, generation of independent sub clon es from an early, non-rearranged tumour progenitor appears to be a common f eature among leukaemias with aggressive clinical behaviour. We speculate on the type of genetic factors which may participate both in the generation o f subclones and also in wider genomic instability and which are Likely to b e required for the aggressive clinical phenotype in children with ALL.