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

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.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001006133 NextSeq 500 74
EGAD00001006134 NextSeq 500 757
EGAD00001006135 NextSeq 500 285
EGAD00001006136 NextSeq 500 24
EGAD00001006137 NextSeq 500 539
EGAD00001006138 NextSeq 500 444
EGAD00010001872 EPIC arrays 32
Publications Citations
Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia.
Nat Cancer 2: 2021 835-852
18
Stem cell-like reprogramming is required for leukemia-initiating activity in B-ALL.
J Exp Med 221: 2024 e20230279
2