Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia.
Date
2021-07-05Author
Turati, VA
Guerra-Assunção, JA
Potter, NE
Gupta, R
Ecker, S
Daneviciute, A
Tarabichi, M
Webster, AP
Ding, C
May, G
James, C
Brown, J
Conde, L
Russell, LJ
Ancliff, P
Inglott, S
Cazzaniga, G
Biondi, A
Hall, GW
Lynch, M
Hubank, M
Macaulay, I
Beck, S
Van Loo, P
Jacobsen, SE
Greaves, M
Herrero, J
Enver, T
Type
Journal Article
Metadata
Show full item recordAbstract
Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We, therefore, investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of cell state accounts for a significant component of bottleneck selection during induction chemotherapy.
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Subject
Burkitt Lymphoma
Cell Cycle
Humans
Induction Chemotherapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Recurrence
Research team
Evol Genomics & Modelling
Biol Childhood Leukaemia
Language
eng
Date accepted
2021-05-11
License start date
2021-07-05
Citation
Nature Cancer, 2021, 2 (8), pp. 835 - 852
Publisher
NATURE PORTFOLIO