@article{5af3fc74f04d43c8882674bfa2d73d46,
title = "Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia",
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.",
author = "Turati, {Virginia A.} and Guerra-Assun{\c c}{\~a}o, {Jos{\'e} Afonso} and Potter, {Nicola E.} and Rajeev Gupta and Simone Ecker and Agne Daneviciute and Maxime Tarabichi and Webster, {Amy P.} and Chuling Ding and Gillian May and Chela James and John Brown and Lucia Conde and Russell, {Lisa J.} and Phil Ancliff and Sarah Inglott and Giovanni Cazzaniga and Andrea Biondi and Hall, {Georgina W.} and Mark Lynch and Mike Hubank and Iain Macaulay and Stephan Beck and {Van Loo}, Peter and Jacobsen, {Sten E.} and Mel Greaves and Javier Herrero and Tariq Enver",
note = "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{\textquoteright}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{\textquoteright}s Horizon 2020 research and innovation program (Marie Sk{\l}odowska-Curie grant agreement no. 747852-SIOMICS), P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation{\textquoteright}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).",
year = "2021",
month = aug,
doi = "10.1038/s43018-021-00219-3",
language = "English",
volume = "2",
pages = "835--852",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "8",
}
