Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

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. U...

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Bibliographic Details
Published in:Leukemia 2016-12, Vol.30 (12), p.2312-2321
Main Authors: Bashford-Rogers, R J M, Nicolaou, K A, Bartram, J, Goulden, N J, Loizou, L, Koumas, L, Chi, J, Hubank, M, Kellam, P, Costeas, P A, Vassiliou, G S
Format: Article
Language:English
Subjects:
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631/67/1990/283/2125
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692/420/2780/2152/2040
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B cells
Cancer Research
Care and treatment
Cell Survival
Chemotherapy
Clone Cells - pathology
Cloning
Critical Care Medicine
Diagnosis
Genomes
Hematology
Humans
Intensive
Internal Medicine
Leukemia
Longitudinal studies
Lymphocytic leukemia
Medicine
Medicine & Public Health
Mutation
Oncology
Original
original-article
Patients
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology
Prognosis
Receptors, Antigen, B-Cell - genetics
Recurrence
Sequence Analysis, DNA
Somatic Hypermutation, Immunoglobulin - genetics
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Summary: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.
ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2016.142