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

Turati, Virginia A., Guerra-Assunção, José Afonso, Potter, Nicola E., Gupta, Rajeev, Ecker, Simone, Daneviciute, Agne, Tarabichi, Maxime, Webster, Amy P., Ding, Chuling, May, Gillian, James, Chela, Brown, John, Conde, Lucia, Russell, Lisa J., Ancliff, Phil, Inglott, Sarah, Cazzaniga, Giovanni, Biondi, Andrea, Hall, Georgina W., Lynch, Mark, Hubank, Mike, Macaulay, Iain, Beck, Stephan, Van Loo, Peter, Jacobsen, Sten E., Greaves, Mel, Herrero, Javier and Enver, Tariq (2021) Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia. Nature Cancer, 2 (8). pp. 835-852. ISSN 2662-1347

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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.

Item Type: Article
Additional Information: Funding Information: The present study was supported by Blood Cancer UK project grants (to T.E., M.G. and S.E.W.J.) and partially supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (grant no. FC001202), the UK Medical Research Council (grant no. FC001202) and the Wellcome Trust (grant no. FC001202). V.A.T. was funded by grants from Children with Cancer UK and Blood Cancer UK, N.P was founded by Gabriel’s Angels, and J.A.G.-A. and L.C. were funded by the Cancer Research UK–UCL Centre Award. M.T. is a postdoctoral fellow supported by the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement no. 747852-SIOMICS), P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support toward the establishment of the Francis Crick Institute and M.G. was supported by the Wellcome Trust. L.J.R was funded by the Kay Kendall Leukaemia Fund and Leuka, G.C. was funded by the Italian Association for Cancer Research grants (IG2017 no. 20564 to A.B. and IG2015 no. 17593 to G.C.). A.B. and G.C. were funded by the Comitato Maria Letizia Verga and S.E.W.J. by the UK Medical Research Council (grant no. MC_UU_12009/5).
Uncontrolled Keywords: oncology,cancer research,medicine(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2730
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 02 Nov 2022 09:30
Last Modified: 07 Nov 2022 00:49
DOI: 10.1038/s43018-021-00219-3

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