Ding LW1, Tan KT1, Sun QY1, Lao ZT1,2, Yang H1, Jiang N3, Chien W4, Xiao JF1, Loh XY1, Huang ML1, Lill M4, Lin DC4, Yeoh AEJ1,3, Koeffler HP1,4.
1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Department of Haematology, Singapore General Hospital, Singapore.
3Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
4Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, USA.
We examined the clonality and clonal evolution of 34 diagnosis-relapse matched paediatric ALL samples as well as BCR/TCR repertoire of an additional 219 paediatric ALL samples at diagnosis. Bi/oligoclonality was prevalent in both cohorts, highlighting the high degree of heterogeneity of paediatric ALL. Bi/oligoclonality has been previously reported in about 40% of paediatric ALL using Sanger sequencing of the IGH loci (van der Velden et al, 2003). Recently, deep sequencing of the IGH loci further revealed the existence of a large number of minor subclonal rearrangements in paediatric ALL patients (Gawad et al, 2012). The prevalence of oligoclonality may facilitate the Darwinian selection/clonal evolution and may play an important role in ALL progression (Ding et al, 2017). The observation that nearly half of the ALL samples carry non-productive BCR/TCR in both alleles or the only expressed dominant allele is interesting and supports the recent hypothesis that BCR may act as a tumour suppressor in most cases of precursor-ALL (Muschen, 2015). Alternatively, high expression of productive BCR in a subset of ALL patients (~10%) suggest their leukaemic cells may dependent on the pre-BCR signalling and may be responsive to ibrutinib-targeted therapy (Kim et al, 2017). The present study highlights the power of examining the BCR/TCR gene rearrangement using transcriptome sequencing. Our study also provides unique insights into paediatric ALL evolution and disease progression, which may enhance our understanding of relapsed ALL and guide better minimal residual disease monitoring.
BCR/T-cell receptor repertoire; clonal evolution; paediatric ALL; relapse