1. Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia
- Author
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Chuling Ding, Mark Lynch, Phil Ancliff, José Afonso Guerra-Assunção, Sten Eirik W. Jacobsen, Nicola E. Potter, Maxime Tarabichi, Amy P. Webster, Peter Van Loo, Agne Daneviciute, Mel Greaves, Rajeev Gupta, Chela James, Stephan Beck, Javier Herrero, Virginia Turati, Giovanni Cazzaniga, Lucia Conde, John Brown, Lisa J. Russell, Iain C. Macaulay, Georgina W. Hall, Andrea Biondi, Mike Hubank, Sarah Inglott, Tariq Enver, Gillian May, Simone Ecker, Turati, V, Guerra-Assuncao, J, Potter, N, Gupta, R, Ecker, S, Daneviciute, A, Tarabichi, M, Webster, A, Ding, C, May, G, James, C, Brown, J, Conde, L, Russell, L, Ancliff, P, Inglott, S, Cazzaniga, G, Biondi, A, Hall, G, Lynch, M, Hubank, M, Macaulay, I, Beck, S, Van Loo, P, Jacobsen, S, Greaves, M, Herrero, J, and Enver, T
- Subjects
Cancer Research ,education.field_of_study ,Tumour heterogeneity ,Genetic heterogeneity ,Population ,Cell Cycle ,Induction chemotherapy ,Cancer ,Induction Chemotherapy ,Cell cycle ,Biology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Burkitt Lymphoma ,Article ,medicine.anatomical_structure ,Oncology ,Recurrence ,RNA-SEQ REVEALS ,medicine ,Cancer research ,Humans ,Cancer epigenetics ,education ,B cell - 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. Enver and colleagues report that epigenetic cell state, rather than genetic diversity, drives bottleneck selection of subclonal genotypes during induction chemotherapy in childhood B-cell precursor acute lymphoblastic leukemia.
- Published
- 2021