Induction chemotherapy does not impact intraclonal heterogeneity in leukaemia

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests 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 mechanisms of selection in childhood B-cell acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual patient leukemias were transplanted into multiple mouse recipients and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has unexpectedly little impact on genetic heterogeneity. However, we discovered extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in untreated BCP-ALL. The spectrum of cell states represented was dramatically reduced following chemotherapy leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. We conclude that epigenetic cell state, not genetic variegation, is the principal substrate for bottleneck selection during induction chemotherapy.EGA study EGAS00001004407