Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

Virginia A. Turati; José Afonso Guerra-Assunção; Nicola E. Potter; Rajeev Gupta; Simone Ecker; Agne Daneviciute; Maxime Tarabichi; Amy P. Webster; Chuling Ding; Gillian May; Chela James; John Brown; Lucia Conde; Lisa J. Russell; Phil Ancliff; Sarah Inglott; Giovanni Cazzaniga; Andrea Biondi; Georgina W. Hall; Mark Lynch; Mike Hubank; Iain Macaulay; Stephan Beck; Peter Van Loo; Sten E. Jacobsen; Mel Greaves; Javier Herrero; Tariq Enver

doi:10.1038/s43018-021-00219-3

Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

Virginia A. Turati, José Afonso Guerra-Assunção, Nicola E. Potter, Rajeev Gupta, Simone Ecker, Agne Daneviciute, Maxime Tarabichi, Amy P. Webster, Chuling Ding, Gillian May, Chela James, John Brown, Lucia Conde, Lisa J. Russell, Phil Ancliff, Sarah Inglott, Giovanni Cazzaniga, Andrea Biondi, Georgina W. Hall, Mark LynchMike Hubank, Iain Macaulay, Stephan Beck, Peter Van Loo, Sten E. Jacobsen, Mel Greaves, Javier Herrero, Tariq Enver

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17 Scopus citations

Abstract

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 the cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

Original language	English (US)
Pages (from-to)	835-852
Number of pages	18
Journal	Nature Cancer
Volume	2
Issue number	8
DOIs	https://doi.org/10.1038/s43018-021-00219-3
State	Published - Aug 2021
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research
General Medicine

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Turati, V. A., Guerra-Assunção, J. A., Potter, N. E., Gupta, R., Ecker, S., Daneviciute, A., Tarabichi, M., Webster, A. P., Ding, C., May, G., James, C., Brown, J., Conde, L., Russell, L. J., Ancliff, P., Inglott, S., Cazzaniga, G., Biondi, A., Hall, G. W., ... Enver, T. (2021). Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia. Nature Cancer, 2(8), 835-852. https://doi.org/10.1038/s43018-021-00219-3

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 2021, 'Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia', Nature Cancer, vol. 2, no. 8, pp. 835-852. https://doi.org/10.1038/s43018-021-00219-3

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abstract = "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 the cell state accounts for a significant component of bottleneck selection during induction chemotherapy.",

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AU - Cazzaniga, Giovanni

AU - Biondi, Andrea

AU - Hall, Georgina W.

AU - Lynch, Mark

AU - Hubank, Mike

AU - Macaulay, Iain

AU - Beck, Stephan

AU - Van Loo, Peter

AU - Jacobsen, Sten E.

AU - Greaves, Mel

AU - Herrero, Javier

AU - Enver, Tariq

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Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

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