Chemotherapy Induces Bottleneck Selection of Cell State in BCP–ALL

Cancers frequently display intratumoral genetic heterogeneity, but analyses of tumor samples from patients who relapsed after chemotherapy suggest a selection process in which specific cancer subclones gain dominance. To investigate the immediate effects of chemotherapy on the genetic and epigenetic landscape of tumor cells that remain post-treatment, Turati and colleagues focused their study on childhood B-cell precursor acute lymphoblastic leukemia (BCP–ALL). Single-cell whole-genome sequencing analysis mapped the clonal architecture of pretreatment samples from patients with BCP–ALL, demonstrating baseline genetic heterogeneity. Leukemic cell genotypes were not found to co-segregate with disease-relevant cell states, as almost all genetic subclones in four of five patient samples seemed to equally comprise the subpopulation of CD19⁺CD34⁺CD38^−/lo leukemic cells, thought to have leukemia-initiating cell potential. In a patient-derived xenograft model, BCP–ALL bone marrow cells were harvested from mice before and after 28 days of treatment with vincristine and dexamethasone, revealing that chemotherapy did not substantially alter subclonal genetic composition. However, residual leukemic cells from treated mice displayed significant transcriptional differences compared with cells from untreated mice, downregulating pathways involved in cell-cycle regulation and cell metabolism, and bulk DNA methylation analysis suggested that epigenetic modifications contributed to transcriptional changes in resistant cells. Moreover, in contrast to heterogeneous untreated cells, treated cells exhibited transcriptional homogeneity, despite mutational heterogeneity. Given previous reports linking cell-cycle stage and drug resistance in BCP–ALL, untreated and treated cells were assigned to cell-cycle phases based on gene expression, uncovering that treated cells were exclusively in G0 phase and enriched for a rare subset of quiescent cells expressing a more primitive differentiation gene expression signature. Based on gene expression, these chemoresistant cells closely resembled a subpopulation of untreated cells, suggesting that chemotherapy induced selection of a preexisting cell state. Together, this work elucidates how chemotherapy selection leads to a genetically heterogeneous but phenotypically homogeneous cell state in childhood BCP–ALL, with clinical implications for how chemotherapy may affect the development of measurable residual disease.

Turati VA, Afonso Guerra-Assunção J, Potter NE, Gupta R, Ecker S, Daneviciute A, et al. Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia. Nat Cancer 2021 Jul 5 [Epub ahead of print].

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