Clonal Heterogeneity and Evolution during Treatment in High Hyperdiploid B-Cell ALL
Dr Margo Aertgeerts from UZ Leuven presented her PhD research in ALL, the most prevalent cancer in the pediatric population. The aetiology of ALL involves the incremental acquisition of mutations by lymphoid progenitor cells, resulting in the formation of a heterogeneous population of leukaemia cells. Each of these cells may harbour distinct mutational profiles, potentially contributing to varying treatment sensitivities. Our hypothesis posits that greater heterogeneity within the leukemic cell population correlates with an increased susceptibility to relapse.
To scrutinize this heterogeneity, we employed single-cell DNA sequencing, which enabled the identification of single nucleotide variants within individual cells. This approach not only facilitated the exploration of diverse mutations but also provided insights into the chronological order in which they were acquired. These findings were subsequently correlated with bone marrow samples obtained from the same patients after the induction phase, where residual leukaemia cells persist. Notably, KRAS-positive cells exhibited reduced sensitivity to induction treatment compared to their NRAS-positive counterparts; however, a favourable response was observed after the initial consolidation phase.
Analysis of a relapsed patient revealed that the clones identified at diagnosis exhibited greater complexity compared to samples from non-relapsed individuals. Tracking these clones from diagnosis through the end of induction to relapse unveiled the presence of a dominant clone at relapse, albeit at a minimal percentage during the diagnostic phase.
Furthermore, a comprehensive examination of proteins in various cell populations revealed distinctions between normal cells and B-ALL cells. Systematic investigation of individual B-ALL samples at different treatment stages, including identification of CD19-negative cells following anti-CD19 CAR-T cell therapy, highlighted the dynamic nature of the leukemic cell population.
In conclusion, our study successfully characterized distinct clones at different disease stages—diagnosis, end of induction, and relapse. Further exploration, particularly of relapse samples, holds promise for refining risk stratification strategies, ultimately enhancing the management of pediatric ALL patients.
Reference:
Aertgeerts M, ASH2023. #1606
With the educational support of:
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