Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse.
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Embargo End Date
ICR Authors
Authors
Bashford-Rogers, RJM
Nicolaou, KA
Bartram, J
Goulden, NJ
Loizou, L
Koumas, L
Chi, J
Hubank, M
Kellam, P
Costeas, PA
Vassiliou, GS
Nicolaou, KA
Bartram, J
Goulden, NJ
Loizou, L
Koumas, L
Chi, J
Hubank, M
Kellam, P
Costeas, PA
Vassiliou, GS
Document Type
Journal Article
Date
2016-12-01
Date Accepted
2016-05-12
Abstract
The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome.
Citation
Leukemia, 2016, 30 (12), pp. 2312 - 2321
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0887-6924
eISSN
1476-5551
Collections
Research Team
Translational Genomics