Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
entrez:
4
11
2021
pubmed:
5
11
2021
medline:
5
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34734190
doi: 10.1038/s43018-021-00219-3
pmc: PMC7611923
mid: EMS124319
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
835-852Subventions
Organisme : Blood Cancer UK
ID : 16001
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : FC001202
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M009033/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_12020
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N000838/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0501838
Pays : United Kingdom
Déclaration de conflit d'intérêts
Competing Interest M.L was an employee of Fluidigm Corporation at the time of the study.
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